Researchers Database

takeda norihiko

    Cavdiology and Metabolism Professor
Last Updated :2021/12/07

Researcher Information

J-Global ID

Research Areas

  • Life sciences / Cardiology

Published Papers

  • Yamato Fukui, Yasushi Hirota, Tomoko Saito-Fujita, Shizu Aikawa, Takehiro Hiraoka, Tetsuaki Kaku, Tomoyuki Hirata, Shun Akaeda, Mitsunori Matsuo, Ryoko Shimizu-Hirota, Norihiko Takeda, Masahito Ikawa, Yutaka Osuga
    Endocrinology 0013-7227 2021/08 
    Abstract Recent studies have demonstrated that the formation of an implantation chamber composed of a uterine crypt, an implantation-competent blastocyst, and uterine glands is a critical step in blastocyst implantation in mice. Leukemia inhibitory factor (LIF) activates signal transducer and activator of transcription 3 (STAT3) precursors via uterine LIF receptors (LIFRs), allowing successful blastocyst implantation. Our recent study revealed that the role of epithelial STAT3 is different from that of stromal STAT3. However, both are essential for blastocyst attachment, suggesting the different roles of epithelial and stromal LIFR in blastocyst implantation. However, how epithelial and stromal LIFR regulate the blastocyst implantation process remains unclear. To investigate the roles of LIFR in the uterine epithelium and stroma, we generated Lifr-floxed/lactoferrin (Ltf)-iCre (Lifr eKO) and Lifr-floxed/anti-Mullerian hormone receptor type 2 (Amhr2)-Cre (Lifr sKO) mice with deleted epithelial and stromal LIFR, respectively. Surprisingly, fertility and blastocyst implantation in the Lifr sKO mice were normal despite stromal STAT3 inactivation. In contrast, blastocyst attachment failed, and no implantation chambers were formed in the Lifr eKO mice with epithelial inactivation of STAT3. In addition, normal responsiveness to ovarian hormones was observed in the peri-implantation uteri of the Lifr eKO mice. These results indicate that the epithelial LIFR-STAT3 pathway initiates the formation of implantation chambers, leading to complete blastocyst attachment, and that stromal STAT3 regulates blastocyst attachment without stromal LIFR control. Thus, uterine epithelial LIFR is critical to implantation chamber formation and blastocyst attachment.
  • Michal Sobecki, Ewelina Krzywinska, Shunmugam Nagarajan, Annette Audigé, Khanh Huỳnh, Julian Zacharjasz, Julien Debbache, Yann Kerdiles, Dagmar Gotthardt, Norihiko Takeda, Joachim Fandrey, Lukas Sommer, Veronika Sexl, Christian Stockmann
    Nature communications 12 (1) 4700 - 4700 2021/08 
    During skin injury, immune response and repair mechanisms have to be coordinated for rapid skin regeneration and the prevention of microbial infections. Natural Killer (NK) cells infiltrate hypoxic skin lesions and Hypoxia-inducible transcription factors (HIFs) mediate adaptation to low oxygen. We demonstrate that mice lacking the Hypoxia-inducible factor (HIF)-1α isoform in NK cells show impaired release of the cytokines Interferon (IFN)-γ and Granulocyte Macrophage - Colony Stimulating Factor (GM-CSF) as part of a blunted immune response. This accelerates skin angiogenesis and wound healing. Despite rapid wound closure, bactericidal activity and the ability to restrict systemic bacterial infection are impaired. Conversely, forced activation of the HIF pathway supports cytokine release and NK cell-mediated antibacterial defence including direct killing of bacteria by NK cells despite delayed wound closure. Our results identify, HIF-1α in NK cells as a nexus that balances antimicrobial defence versus global repair in the skin.
  • Neil J Stewart, Tatsuyuki Sato, Norihiko Takeda, Hiroshi Hirata, Shingo Matsumoto
    Antioxidants & redox signaling 2021/07 
    Significance: Magnetic resonance imaging (MRI) with hyperpolarized 13C-labelled redox-sensitive metabolic tracers can provide non-invasive functional imaging biomarkers reflecting; tissue redox state, oxidative stress, and inflammation, among others. The capability to use endogenous metabolites as 13C-enriched imaging tracers without structural modification makes hyperpolarized 13C MRI a promising tool to evaluate redox state in patients with various diseases. Recent Advances: Recent studies have demonstrated the feasibility of in vivo metabolic imaging of 13C-labelled tracers polarized by parahydrogen-induced polarization techniques, which offer a cost-effective alternative to the more widely-used dissolution dynamic nuclear polarization-based hyperpolarizers. Critical Issues: Although the fluxes of many metabolic pathways reflect the change in tissue redox state, they are not functionally specific. In the present review, we summarize recent challenges in the development of specific 13C metabolic tracers for biomarkers of redox state, including that for detecting reactive oxygen species. Future Directions: Applications of hyperpolarized 13C metabolic MRI to evaluate redox state have only just begun to be investigated. The possibility to gain a comprehensive understanding of the correlations between tissue redox potential and metabolism under different pathological conditions by using hyperpolarized 13C MRI is promoting its interest in the clinical arena, along with its non-invasive biomarkers to evaluate the extent of disease and treatment response.
  • Masato Ishizuka, Mutsuo Harada, Seitaro Nomura, Toshiyuki Ko, Yuichi Ikeda, Jiaxi Guo, Satoshi Bujo, Haruka Yanagisawa-Murakami, Masahiro Satoh, Shintaro Yamada, Hidetoshi Kumagai, Yoshihiro Motozawa, Hironori Hara, Takayuki Fujiwara, Tatsuyuki Sato, Norifumi Takeda, Norihiko Takeda, Kinya Otsu, Hiroyuki Morita, Haruhiro Toko, Issei Komuro
    Scientific reports 11 (1) 12340 - 12340 2021/06
  • Neil J Stewart, Hitomi Nakano, Shuto Sugai, Mitsushi Tomohiro, Yuki Kase, Yoshiki Uchio, Toru Yamaguchi, Yujirou Matsuo, Tatsuya Naganuma, Norihiko Takeda, Ikuya Nishimura, Hiroshi Hirata, Takuya Hashimoto, Shingo Matsumoto
    Chemphyschem : a European journal of chemical physics and physical chemistry 22 (10) 905 - 905 2021/05 
    The front cover artwork is provided by the group of Dr. Neil J. Stewart, Prof. Hiroshi Hirata, and Dr. Shingo Matsumoto (Hokkaido University, Japan) as well as Dr. Takuya Hashimoto (Chiba University, Japan). The image shows hyperpolarized 13 C fumarate metabolism to hyperpolarized 13 C malate, which is released into the extracellular space in regions of necrotic cell death, where the cell membrane is disrupted. Read the full text of the Article at 10.1002/cphc.202001038.
  • Tatsunori Suzuki, Takahiro Kishikawa, Tatsuyuki Sato, Norihiko Takeda, Yuki Sugiura, Takahiro Seimiya, Kazuma Sekiba, Motoko Ohno, Takuma Iwata, Rei Ishibashi, Motoyuki Otsuka, Kazuhiko Koike
    Cancer gene therapy 2021/04 
    Mutational activation of the KRAS gene occurs in almost all pancreatic ductal adenocarcinoma (PDAC) and is the earliest molecular event in their carcinogenesis. Evidence has accumulated of the metabolic reprogramming in PDAC, such as amino acid homeostasis and autophagic flux. However, the biological effects of KRAS mutation on metabolic reprogramming at the earlier stages of PDAC carcinogenesis are unclear. Here we report dynamic metabolic reprogramming in immortalized human non-cancerous pancreatic ductal epithelial cells, in which a KRAS mutation was induced by gene-editing, which may mimic early pancreatic carcinogenesis. Similar to the cases of PDAC, KRAS gene mutation increased the dependency on glucose and glutamine for maintaining the intracellular redox balance. In addition, the intracellular levels of amino acids were significantly decreased because of active protein synthesis, and the cells required greater autophagic flux to maintain their viability. The lysosomal inhibitor chloroquine significantly inhibited cell proliferation. Therefore, metabolic reprogramming is an early event in carcinogenesis initiated by KRAS gene mutation, suggesting a rationale for the development of nutritional interventions that suppress or delay the development of PDAC.
  • Masamitsu Harada, Jun Nagai, Riho Kurata, Xiaofeng Cui, Takayuki Isagawa, Hiroaki Semba, Yasuhiro Yoshida, Norihiko Takeda, Koji Maemura, Tomo Yonezawa
    International journal of molecular sciences 22 (5) 2021/02 
    Repressor element-1 (RE-1) or neural restrictive silencer element (NRSE) bound with a zinc finger transcription repressor, RE-1 silencing transcription factor (REST, also known as neural restrictive silencer factor, NRSF) has been identified as a fundamental repressor element in many genes, including neuronal genes. Genes regulated by REST/NRSF regulate multifaceted neuronal phenotypes, and their defects in the machinery cause neuropathies, disorders of neuron activity), autism and so on. In REST repressions, the N-terminal repressor domain recruits Sin3B via its paired amphipathic helix 1 (PAH1) domain, which plays an important role as a scaffold for histone deacetylase 1 and 2. This machinery has a critical role in maintaining neuronal robustness. In this study, in order to establish protein-protein interaction assays mimicking a binding surface between Sin3B and REST, we selected important amino acids from structural information of the PAH1/REST complex and then tried to reconstitute it using recombinant short peptides derived from PAH1/REST. Initially, we validated whether biotinylated REST interacts with glutathione S-transferase (GST)-tagged PAH1 and whether another PAH1 peptide (PAH1-FLAG) competitively binds with biotinylated REST using surface plasmon resonance (SPR). We observed a direct interaction and competitive binding of two PAH1 peptides. Secondly, in order to establish a high-throughput and high-dynamic-range assay, we utilized an easily performed novel time-resolved fluorescence energy transfer (TR-FRET) assay, and closely monitored this interaction. Finally, we succeeded in establishing a novel high-quality TR-FRET assay and a novel interaction assay based on SPR.
  • Masato Ishizuka, Mutsuo Harada, Seitaro Nomura, Toshiyuki Ko, Yuichi Ikeda, Jiaxi Guo, Satoshi Bujo, Haruka Yanagisawa-Murakami, Masahiro Satoh, Shintaro Yamada, Hidetoshi Kumagai, Yoshihiro Motozawa, Hironori Hara, Takayuki Fujiwara, Tatsuyuki Sato, Norifumi Takeda, Norihiko Takeda, Kinya Otsu, Hiroyuki Morita, Haruhiro Toko, Issei Komuro
    Scientific reports 11 (1) 3426 - 3426 2021/02 
    Most seven transmembrane receptors (7TMRs) are G protein-coupled receptors; however, some 7TMRs evoke intracellular signals through β-arrestin as a biased receptor. As several β-arrestin-biased agonists have been reported to be cardioprotective, we examined the role of the chemokine receptor CXCR7 as a β-arrestin-biased receptor in the heart. Among 510 7TMR genes examined, Cxcr7 was the most abundantly expressed in the murine heart. Single-cell RNA-sequencing analysis revealed that Cxcr7 was abundantly expressed in cardiomyocytes and fibroblasts. Cardiomyocyte-specific Cxcr7 null mice showed more prominent cardiac dilatation and dysfunction than control mice 4 weeks after myocardial infarction. In contrast, there was no difference in cardiac phenotypes between fibroblast-specific Cxcr7-knockout mice and control mice even after myocardial infarction. TC14012, a specific agonist of CXCR7, significantly recruited β-arrestin to CXCR7 in CXCR7-expressing cells and activated extracellular signal-regulated kinase (ERK) in neonatal rat cardiomyocytes. Cxcr7 expression was significantly increased and ERK was activated in the border zone of the heart in control, but not Cxcr7 null mice. These results indicate that the abundantly expressed CXCR7 in cardiomyocytes may play a protective role in the heart as a β-arrestin-biased receptor and that CXCR7 may be a novel therapeutic target for myocardial infarction.
  • Shun Akaeda, Yasushi Hirota, Yamato Fukui, Shizu Aikawa, Ryoko Shimizu-Hirota, Tetsuaki Kaku, Mona Gebril, Tomoyuki Hirata, Takehiro Hiraoka, Mitsunori Matsuo, Hirofumi Haraguchi, Mayuko Saito-Kanatani, Norihiko Takeda, Tomoyuki Fujii, Yutaka Osuga
    EMBO reports 22 (2) e50927  2021/02 
    Retinoblastoma protein (RB) encoded by Rb1 is a prominent inducer of cell cycle arrest (CCA). The hormone progesterone (P4 ) promotes CCA in the uterine epithelium and previous studies indicated that P4 activates RB by reducing the phosphorylated, inactive form of RB. Here, we show that embryo implantation is impaired in uterine-specific Rb1 knockout mice. We observe persistent cell proliferation of the Rb1-deficient uterine epithelium until embryo attachment, loss of epithelial necroptosis, and trophoblast phagocytosis, which correlates with subsequent embryo invasion failure, indicating that Rb1-induced CCA and necroptosis of uterine epithelium are involved in embryo invasion. Pre-implantation P4 supplementation is sufficient to restore these defects and embryo invasion. In Rb1-deficient uterine epithelial cells, TNFα-primed necroptosis is impaired, which is rescued by the treatment with a CCA inducer thymidine or P4 through the upregulation of TNF receptor type 2. TNFα is expressed in the luminal epithelium and the embryo at the embryo attachment site. These results provide evidence that uterine Rb1-induced CCA is involved in TNFα-primed epithelial necroptosis at the implantation site for successful embryo invasion.
  • Ryota Takahashi, Hideaki Ijichi, Makoto Sano, Koji Miyabayashi, Dai Mohri, Jinsuk Kim, Gen Kimura, Takuma Nakatsuka, Hiroaki Fujiwara, Keisuke Yamamoto, Yotaro Kudo, Yasuo Tanaka, Keisuke Tateishi, Yousuke Nakai, Yasuyuki Morishita, Katsura Soma, Norihiko Takeda, Harold L Moses, Hiroyuki Isayama, Kazuhiko Koike
    Scientific reports 10 (1) 21194 - 21194 2020/12 
    Pancreatic cancer is one of the malignant diseases with the worst prognosis. Resistance to chemotherapy is a major difficulty in treating the disease. We analyzed plasma samples from a genetically engineered mouse model of pancreatic cancer and found soluble vascular cell adhesion molecule-1 (sVCAM-1) increases in response to gemcitabine treatment. VCAM-1 was expressed and secreted by murine and human pancreatic cancer cells. Subcutaneous allograft tumors with overexpression or knock-down of VCAM-1, as well as VCAM-1-blocking treatment in the spontaneous mouse model of pancreatic cancer, revealed that sVCAM-1 promotes tumor growth and resistance to gemcitabine treatment in vivo but not in vitro. By analyzing allograft tumors and co-culture experiments, we found macrophages were attracted by sVCAM-1 to the tumor microenvironment and facilitated resistance to gemcitabine in tumor cells. In a clinical setting, we found that the change of sVCAM-1 in the plasma of patients with advanced pancreatic cancer was an independent prognostic factor for gemcitabine treatment. Collectively, gemcitabine treatment increases the release of sVCAM-1 from pancreatic cancer cells, which attracts macrophages into the tumor, thereby promoting the resistance to gemcitabine treatment. sVCAM-1 may be a potent clinical biomarker and a potential target for the therapy in pancreatic cancer.
  • Mona Gebril, Yasushi Hirota, Shizu Aikawa, Yamato Fukui, Tetsuaki Kaku, Mitsunori Matsuo, Tomoyuki Hirata, Shun Akaeda, Takehiro Hiraoka, Ryoko Shimizu-Hirota, Norihiko Takeda, Tamer Taha, Osama Al Balah, Mohamed Amr H Elnoury, Tomoyuki Fujii, Yutaka Osuga
    Endocrinology 161 (12) 2020/12 
    Progesterone receptor (PGR) is indispensable for pregnancy in mammals. Uterine PGR responds to the heightened levels of ovarian progesterone (P4) after ovulation and regulates uterine gene transcription for successful embryo implantation. Although epithelial and stromal P4-PGR signaling may interact with each other to form appropriate endometrial milieu for uterine receptivity and the subsequent embryo attachment, it remains unclear what the specific roles of epithelial P4-PGR signaling in the adult uterus are. Here we generated mice with epithelial deletion of Pgr in the adult uterus (Pgrfl/flLtfCre/+ mice) by crossing Pgr-floxed and Ltf-Cre mice. Pgrfl/flLtfCre/+ mice are infertile due to the impairment of embryo attachment. Pgrfl/flLtfCre/+ uteri did not exhibit epithelial growth arrest, suggesting compromised uterine receptivity. Both epithelial and stromal expressions of P4-responsive genes decreased in Pgrfl/flLtfCre/+ mice during the peri-implantation period, indicating that epithelial Pgr deletion affects not only epithelial but stromal P4 responsiveness. In addition, uterine LIF, an inducer of embryo attachment, was decreased in Pgrfl/flLtfCre/+ mice. The RNA-seq analysis using luminal epithelial specimens dissected out by laser capture microdissection revealed that the signaling pathways related to extracellular matrix, cell adhesion, and cell proliferation are altered in Pgr fl/flLtf Cre/+ mice. These findings suggest that epithelial PGR controls both epithelial and stromal P4 responsiveness and epithelial cell differentiation, which provides normal uterine receptivity and subsequent embryo attachment.
  • Shuoyu Wei, Takayuki Isagawa, Masamichi Eguchi, Daisuke Sato, Hiroto Tsukano, Keishi Miyata, Yuichi Oike, Norihiko Takeda, Satoshi Ikeda, Hiroaki Kawano, Koji Maemura
    Biomedicines 8 (11) 2020/11 
    Macrophages in the atheroma region produce matrix metalloproteinases (MMPs) and decrease plaque stability. Tissue oxygen tension decreases in the arterial wall of the atherosclerotic region. Hypoxia inducible factor (HIF)-1α plays a critical role in the transcriptional activation of hypoxia inducible genes. However, the precise roles of HIF-1α independent pathways in hypoxic responses are largely unknown. Xanthine oxidase (XO) is an enzyme that utilizes molecular oxygen and produces reactive oxygen species (ROS). Here, we show that ROS derived from XO increases MMP-3, -10, and -13 expression in murine macrophages. We found that the transcript levels of macrophage MMP-3, -10, and -13 were increased in hypoxic conditions. Hypoxia induced MMP expression in HIF-1α deficient macrophages. N-acetylcysteine (NAC) or febuxostat, an XO inhibitor, suppressed MMP expression in murine macrophages. Febuxostat decreased the incidence of plaque rupture in apolipoprotein-E-deficient mice. Our results indicate that febuxostat stabilized atherosclerotic plaque via suppressing the activities of macrophage MMP-9 and -13. Febuxostat administration is a potential therapeutic option in the management of atherosclerotic patients.
  • シャーガス慢性心筋炎の病態形成機構
    中釜 悠, 伊藤 正道, 仁田原 裕子, Candray Katherine, Rodriguez Stanley, 武田 憲彦, 嶋田 淳子, 金子 明, 城戸 康年
    日本小児循環器学会雑誌 (NPO)日本小児循環器学会 36 (Suppl.2) s2 - 218 0911-1794 2020/11
  • Takehiro Hiraoka, Yasushi Hirota, Yamato Fukui, Mona Gebril, Tetsuaki Kaku, Shizu Aikawa, Tomoyuki Hirata, Shun Akaeda, Mitsunori Matsuo, Hirofumi Haraguchi, Mayuko Saito-Kanatani, Ryoko Shimizu-Hirota, Norihiko Takeda, Osamu Yoshino, Tomoyuki Fujii, Yutaka Osuga
    Scientific reports 10 (1) 15523 - 15523 2020/09 
    Although it has been reported that uterine signal transducer and activator of transcription 3 (STAT3) is essential for embryo implantation, the exact roles of uterine epithelial and stromal STAT3 on embryo implantation have not been elucidated. To address this issue, we generated Stat3-floxed/Ltf-iCre (Stat3-eKO), Stat3-floxed/Amhr2-Cre (Stat3-sKO), and Stat3-floxed/Pgr-Cre (Stat3-uKO) mice to delete Stat3 in uterine epithelium, uterine stroma, and whole uterine layers, respectively. We found that both epithelial and stromal STAT3 have critical roles in embryo attachment because all the Stat3-eKO and Stat3-sKO female mice were infertile due to implantation failure without any embryo attachment sites. Stat3-eKO uteri showed indented structure of uterine lumen, indicating the role of epithelial STAT3 in slit-like lumen formation in the peri-implantation uterus. Stat3-sKO uteri exhibited hyper-estrogenic responses and persistent cell proliferation of the epithelium in the peri-implantation uterus, suggesting the role of stromal STAT3 in uterine receptivity. In addition, Stat3-uKO female mice possessed not only the characteristic of persistent epithelial proliferation but also that of indented structure of uterine lumen. These findings indicate that epithelial STAT3 controls the formation of slit-like structure in uterine lumen and stromal STAT3 suppresses epithelial estrogenic responses and cell proliferation. Thus, epithelial and stromal STAT3 cooperatively controls uterine receptivity and embryo attachment through their different pathways.
  • ヒトIL-18特異的シグナルを検出する新規リポーター細胞の樹立および独自ライブラリーを用いた創薬への取り組み
    倉田 里穂, 原田 将光, 砂河 孝行, 仙波 宏章, 武田 憲彦, 前村 浩二, 米澤 朋
    別冊Bio Clinica: 慢性炎症と疾患 (株)北隆館 9 (1) 96 - 101 2020/08 
  • ヒトIL-18特異的シグナルを検出する新規リポーター細胞の樹立および独自ライブラリーを用いた創薬への取り組み
    倉田 里穂, 原田 将光, 砂河 孝行, 仙波 宏章, 武田 憲彦, 前村 浩二, 米澤 朋
    別冊Bio Clinica: 慢性炎症と疾患 (株)北隆館 9 (1) 96 - 101 2020/08 
  • Keita Okada, Daisuke Mori, Yuma Makii, Hideki Nakamoto, Yasutaka Murahashi, Fumiko Yano, Song Ho Chang, Yuki Taniguchi, Hiroshi Kobayashi, Hiroaki Semba, Norihiko Takeda, Wen Piao, Kenjiro Hanaoka, Tetsuo Nagano, Sakae Tanaka, Taku Saito
    Scientific reports 10 (1) 5425 - 5425 2020/03 [Refereed][Not invited]
    HIF-1α, an essential transcription factor under hypoxic condition, is indispensable for chondrocytes during skeletal development but its expression and roles in articular chondrocytes are yet to be revealed. We examined HIF-1α protein expression and the hypoxic condition during mouse osteoarthritis (OA) development using state of the art hypoxic probes and found that its expression decreased as OA progressed, coinciding with the change in hypoxic conditions in articular cartilage. Gain- and loss-of-function of HIF-1α in cell culture experiments showed that HIF-1α suppressed catabolic genes such as Mmp13 and Hif2a. We confirmed these anticatabolic effects by measuring glycosaminoglycan release from wild type and conditional knock-out mice femoral heads cultured ex vivo. We went on to surgically induce OA in mice with chondrocyte-specific deletion of Hif1a and found that the development of OA was exacerbated. Increased expression of catabolic factors and activation of NF-κB signalling was clearly evident in the knock-out mice. By microarray analysis, C1qtnf3 was identified as a downstream molecule of HIF-1α, and experiments showed it exerted anti-catabolic effects through suppression of NF-κB. We conclude that HIF-1α has an anti-catabolic function in the maintenance of articular cartilage through suppression of NF-κB signalling.
  • Keisuke Okabe, Hugh Fukada, Ikue Tai-Nagara, Tomofumi Ando, Takao Honda, Kazunori Nakajima, Norihiko Takeda, Guo-Hua Fong, Masatsugu Ema, Yoshiaki Kubota
    Developmental biology 459 (2) 65 - 71 2020/03 [Refereed][Not invited]
    Vascular endothelial growth factor (VEGF) is a potent mitogen critical for angiogenesis and organogenesis. Deletion or inhibition of VEGF during development not only profoundly suppresses vascular outgrowth, but significantly affects the development and function of various organs. In the brain, VEGF is thought to not only promote vascular growth, but also directly act on neurons as a neurotrophic factor by activating VEGF receptors. In the present study, we demonstrated that deletion of VEGF using hGfap-Cre line, which recombines genes specifically in cortical and hippocampal neurons, severely impaired brain organization and vascularization of these regions. The mutant mice had motor deficits, with lethality around the time of weaning. Multiple reporter lines indicated that VEGF was highly expressed in neurons, but that its cognate receptors, VEGFR1 and 2 were exclusive to endothelial cells in the brain. In accordance, mice lacking neuronal VEGFR1 and VEGFR2 did not exhibit neuronal deformities or lethality. Taken together, our data suggest that neuron-derived VEGF contributes to cortical and hippocampal development likely through angiogenesis independently of direct neurotrophic effects mediated by VEGFR1 and 2.
  • Masamitsu Harada, Jun Nagai, Riho Kurata, Kenji Shimizu, Xiaofeng Cui, Takayuki Isagawa, Hiroaki Semba, Jun Ishihara, Yasuhiro Yoshida, Norihiko Takeda, Koji Maemura, Tomo Yonezawa
    Marine drugs 18 (3) 2020/03 [Refereed][Not invited]
    Toxoplasma gondii is a major protozoan parasite and infects human and many other warm-blooded animals. The infection leads to Toxoplasmosis, a serious issue in AIDS patients, organ transplant recipients and pregnant women. Neospora caninum, another type of protozoa, is closely related to Toxoplasma gondii. Infections of the protozoa in animals also causes serious diseases such as Encephalomyelitis and Myositis-Polyradiculitis in dogs or abortion in cows. Both Toxoplasma gondii and Neospora caninum have similar nucleoside triphosphate hydrolases (NTPase), NcNTPase and TgNTPase-I in Neospora caninum and Toxoplasma gondii, respectively. These possibly play important roles in propagation and survival. Thus, we targeted the enzymes for drug discovery and tried to establish a novel high-standard assay by a combination of original biochemical enzyme assay and fluorescent assay to determine ADP content. We then validated whether or not it can be applied to high-throughput screening (HTS). Then, it fulfilled criterion to carry out HTS in both of the enzymes. In order to identify small molecules having inhibitory effects on the protozoan enzyme, we also performed HTS using two synthetic compound libraries and an extract library derived from marine bacteria and then, identified 19 compounds and 6 extracts. Nagasaki University collected many extracts from over 18,000 marine bacteria found in local Omura bay, and continues to compile an extensive collection of synthetic compounds from numerous drug libraries established by Japanese chemists.
  • Yu Nakagama, Norihiko Takeda, Seishi Ogawa, Hiroyuki Takeda, Yoshiyuki Furutani, Toshio Nakanishi, Tatsuyuki Sato, Yoichiro Hirata, Akira Oka, Ryo Inuzuka
    Molecular genetics & genomic medicine 8 (3) e1107  2020/03 [Refereed][Not invited]
    BACKGROUND: Variants in the LZTR1 (leucine-zipper-like transcription regulator 1) gene (OMIM #600574) have been reported in recessive Noonan syndrome patients. In vivo evidence from animal models to support its causative role is lacking. METHODS: By CRISPR-Cas9 genome editing, we generated lztr1-mutated zebrafish (Danio rerio). Analyses of histopathology and downstream signaling were performed to investigate the pathogenesis of cardiac and extracardiac abnormalities in Noonan syndrome. RESULTS: A frameshift deletion allele was created in the zebrafish lztr1. Crosses of heterozygotes obtained homozygous lztr1 null mutants that modeled LZTR1 loss-of-function. Histological analyses of the model revealed ventricular hypertrophy, the deleterious signature of Noonan syndrome-associated cardiomyopathy. Further, assessment for extracardiac abnormalities documented multiple vascular malformations, resembling human vascular pathology caused by RAS/MAPK activation. Due to spatiotemporal regulation of LZTR1, its downstream function was not fully elucidated from western blots of adult tissue. CONCLUSION: Our novel zebrafish model phenocopied human recessive Noonan syndrome and supported the loss-of-function mechanism of disease-causing LZTR1 variants. The discovery of vascular malformations in mutants calls for the clinical follow-up of patients to monitor for its emergence. The model will serve as a novel platform for investigating the pathophysiology linking RAS/MAPK signaling to cardiac and vascular pathology.
  • Mitsunori Matsuo, Yasushi Hirota, Yamato Fukui, Hidetoshi Fujita, Tomoko Saito-Fujita, Tetsuaki Kaku, Mona Gebril, Tomoyuki Hirata, Shun Akaeda, Takehiro Hiraoka, Tomoki Tanaka, Hirofumi Haraguchi, Mayuko Saito-Kanatani, Ryoko Shimizu-Hirota, Norihiko Takeda, Tomoyuki Fujii, Yutaka Osuga
    Endocrinology 161 (2) 0013-7227 2020/02 [Refereed][Not invited]
    Progestogens including progesterone (P4) and levonorgestrel (LNG) are clinically used for multiple purposes such as contraception and infertility treatment. The effects of progestogens on the uterus remains to be elucidated. Here we examine the effect of excessive progestogen administration on embryo implantation focusing on the function of uterine leukemia inhibitory factor (LIF), a cytokine that is induced by estrogen and essential for embryo attachment. Treatment of wild-type (WT) female mice with vehicle (control), LNG at the dose of 300 μg/kg/day and P4 at the dose of 10 mg/day from day 1 to day 4 of pregnancy was conducted. LNG-treated and P4-treated mice showed embryo attachment failure on day 5 of pregnancy (The rate of mice with embryo attachment sites [%MAS], 11% and 13%, respectively), while all the control mice had normal attachment sites. Uterine LIF expression was significantly reduced in LNG-treated and P4-treated mice on day 4 evening. Administration of recombinant LIF (rLIF) at the dose of 24 μg/day on day 4 significantly rescued embryo attachment failure in LNG-treated and P4-treated mice (%MAS, 80% and 75%, respectively). Estradiol (E2) administration also rescued embryo attachment failure in LNG-treated mice (%MAS, 83%). Furthermore, excess P4 treatment before implantation decreased decidual P4 receptor (PGR) expression and induced decidualization defect apart from LIF downregulation. These findings indicate that progestogens cause embryo attachment inhibition through downregulation of uterine LIF expression and compromised decidualization through downregulation of PGR independently of LIF reduction. This study may contribute to a better understanding of contraceptive action of progestogens.
  • Riho Kurata, Kenji Shimizu, Xiaofeng Cui, Masamitsu Harada, Takayuki Isagawa, Hiroaki Semba, Jun Ishihara, Koji Yamada, Jun Nagai, Yasuhiro Yoshida, Norihiko Takeda, Koji Maemura, Tomo Yonezawa
    Marine drugs 18 (1) 2020/01 [Refereed][Not invited]
    Very recently, the immunotherapies against cancer, autoimmune diseases, and infection have been feasible and promising. Thus, we have examined the possibility whether or not human gamma delta T cells can be applied for the novel immunotherapies. We previously established the cells stably maintaining NFkB-driven human secreted embryonic alkaline phosphatase (SEAP) expression. The cells can be used to determine the transcription activity of NFkB with high-standard dynamic range and accuracy. Because IL-18 is a kind of cytokines that enhances cytotoxicity and activity of human gamma delta T cells through NFkB activation, we have focused on the activity and signaling of IL-18. In this study, we modified the previous reporter cell that can determine the transcription activity of NFkB to express two subunits consisted of human IL-18 receptor. The modified cells secreted SEAP in response to treatment with human recombinant IL-18 in a concentration-dependent manner. We also observed the concentration-dependently enhancement of NFkB activity in the cells treated with mouse recombinant IL-18 although the affinity was lower compared to human recombinant IL-18. We also previously established the cells stably expressing and secreting human recombinant IL-18 and then validated whether or not the conditioned medium from the cells activate NFkB transcription activity using this assay. Our university has kept collecting many extracts from over 18,000 marine bacteria in our local sea around Omura bay-fungi, plants for Chinese herbal medicine, and so on-and also have kept gathering synthetic compounds from many Japanese chemists as drug libraries. Finally, in order to identify drugs mimicking IL-18 biological activity or possessing inhibitory effects on IL-18-induced NFkB, we demonstrated drug screening using number of extracts derived from marine bacteria and synthetic compounds.
  • Norihiko Takeda
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica 155 (1) 26 - 29 2020 [Refereed][Not invited]
    A molecular oxygen is essential to keep a physiological activity of each organ or a cell. There exists a heterogeneity in a level of oxygen concentration in each organ. In addition, tissue oxygen concentration fluctuates dynamically during physiological activities or in pathological processes. A decrease in tissue oxygen concentration, termed as hypoxia, significantly influences the function in each organ or cell. For example, a transcript level in each gene tends to be reduced under hypoxic condition. On the other hand, some of the gene expressions are increased significantly in hypoxia, which are termed as hypoxia responsive genes. A group of transcription factor, hypoxia inducible factor (HIF)-1α and HIF-2α play a critical role in the transactivation processes of hypoxia responsive genes. Recently, the molecular processes have been elucidated by which hypoxic environment activates HIF-1α or HIF-2α activity. A preclinical animal model revealed that HIF-α signal plays a critical role in inflammation or tissue remodeling. While HIF-1α and HIF-2α usually work synergistically in inducing their target gene expressions, macrophage HIF-1α and HIF-2α act antagonistically with regard to the synthesis of nitric oxide, a potent inflammatory mediator. This review summarizes the current understanding on the roles of HIF-α mediated hypoxic responses in inflammation or tissue remodeling.
  • Hisataka Maki, Norihiko Takeda
    International heart journal 61 (2) 197 - 198 2020 [Refereed][Not invited]
  • Shunji Nishide, Shinji Matsunaga, Masayuki Shiota, Takehiro Yamaguchi, Shojiro Kitajima, Yoichi Maekawa, Norihiko Takeda, Michio Tomura, Junji Uchida, Katsuyuki Miura, Tatsuya Nakatani, Shuhei Tomita
    iScience 21 205 - 205 2019/11 [Refereed][Not invited]
  • Shunji Nishide, Shinji Matsunaga, Masayuki Shiota, Takehiro Yamaguchi, Shojiro Kitajima, Yoichi Maekawa, Norihiko Takeda, Michio Tomura, Junji Uchida, Katsuyuki Miura, Tatsuya Nakatani, Shuhei Tomita
    iScience 19 940 - 954 2019/09 [Refereed][Not invited]
    The tumor microenvironment (TME) polarizes tumor-infiltrating macrophages toward tumor support. Macrophage-abundant tumors are highly malignant and are the cause of poor prognosis and therapeutic resistance. In this study, we show that the prolyl hydroxylase (PHD) inhibitor FG-4592 (FG) inhibits tumor growth of macrophage-abundant tumors and prolongs mouse survival. FG not only normalizes tumor vessels and improves tumor oxygenation but also directly affects macrophages and activates phagocytosis through the PHD-hypoxia-inducible factor (HIF) axis. Remarkably, FG can promote phagocytic ability of the Ly6Clo subset of tumor-infiltrating macrophages, leading to tumor growth inhibition. Moreover, Ly6Cneg macrophages contributed to blood vessel normalization. Using a malignant tumor mouse model, we characterized macrophage function and subsets. Altogether, our findings suggest that the PHD inhibitor can promote the anti-tumor potential of macrophages to improve cancer therapy.
  • 哺乳動物の心臓の燃料としての乳酸(Lactate as a fuel for the mammalian heart)
    中釜 悠, 武田 憲彦, 城戸 康年, 佐藤 達之, 犬塚 亮, 小室 一成
    日本生化学会大会プログラム・講演要旨集 92回 [2T02m - 03] 2019/09
  • 哺乳動物の心臓の燃料としての乳酸(Lactate as a fuel for the mammalian heart)
    中釜 悠, 武田 憲彦, 城戸 康年, 佐藤 達之, 犬塚 亮, 小室 一成
    日本生化学会大会プログラム・講演要旨集 92回 [2T02m - 03] 2019/09 [Refereed][Not invited]
  • Kenichi Okamura, Yu Nakagama, Norihiko Takeda, Katsura Soma, Tatsuyuki Sato, Takayuki Isagawa, Yasutoshi Kido, Masaya Sakamoto, Ichiro Manabe, Yasutaka Hirata, Issei Komuro, Minoru Ono
    Journal of pharmacological sciences 141 (1) 56 - 63 2019/09 [Refereed][Not invited]
    Concomitant heart failure is associated with poor clinical outcome in dialysis patients. The arteriovenous shunt, created as vascular access for hemodialysis, increases ventricular volume-overload, predisposing patients to developing cardiac dysfunction. The integral function of mitochondrial respiration is critically important for the heart to cope with hemodynamic overload. The involvement, however, of mitochondrial activity or reactive oxygen species (ROS) in the pathogenesis of ventricular-overload-induced heart failure has not been fully elucidated. We herein report that disorganization of mitochondrial respiration increases mitochondrial ROS production in the volume-overloaded heart, leading to ventricular dysfunction. We adopted the murine arteriovenous fistula (AVF) model, which replicates the cardinal features of volume-overload-induced ventricular dysfunction. Enzymatic assays of cardiac mitochondria revealed that the activities of citrate synthase and NADH-quinone reductase (complex Ⅰ) were preserved in the AVF heart. In contrast, the activity of NADH oxidase supercomplex was significantly compromised, resulting in elevated ROS production. Importantly, the antioxidant N-acetylcysteine prevented the development of ventricular dilatation and cardiac dysfunction, suggesting a pathogenic role for ROS in dialysis-related cardiomyopathy. A cardioprotective effect was also observed in metformin-treated mice, illuminating its potential use in the management of heart failure complicating diabetic patients on dialysis.
  • Masaki Wake, Norihiko Takeda, Takayuki Isagawa, Tatsuyuki Sato, Yu Nakagama, Masaki Suimye Morioka, Yasushi Hirota, Masataka Asagiri, Koji Maemura, Ichiro Manabe, Kazuaki Tanabe, Issei Komuro
    International heart journal 60 (4) 958 - 963 1349-2365 2019/07 [Refereed][Not invited]
    Myocardial infarction (MI) occurs when the heart muscle is severely damaged due to a decrease in blood flow from the coronary arteries. During recovery from an MI, cardiac fibroblasts become activated and produce extracellular matrices, contributing to the wound healing process in the damaged heart. Inappropriate activation of the fibroblasts leads to excessive fibrosis in the heart. However, the molecular pathways by which cardiac fibroblasts are activated have not yet been fully elucidated.Here we show that serum deprivation, which recapitulates the cellular microenvironment of the MI area, strikingly induces collagen production in C3H/10T1/2 cells. Based on transcriptomic and pharmacological studies, we found that cell cycle perturbation is directly linked to collagen production in fibroblasts. Importantly, collagen synthesis is increased independently of the transcriptional levels of type I collagen genes. These results reveal a novel mode of fibroblast activation in the ischemic area, which will allow us to gain insights into the molecular mechanisms underlying cardiac fibrosis and establish a basis for anti-fibrotic therapy.
  • Hajime Abe, Norihiko Takeda, Takayuki Isagawa, Hiroaki Semba, Satoshi Nishimura, Masaki Suimye Morioka, Yu Nakagama, Tatsuyuki Sato, Katsura Soma, Katsuhiro Koyama, Masaki Wake, Manami Katoh, Masataka Asagiri, Michael L Neugent, Jung-Whan Kim, Christian Stockmann, Tomo Yonezawa, Ryo Inuzuka, Yasushi Hirota, Koji Maemura, Takeshi Yamashita, Kinya Otsu, Ichiro Manabe, Ryozo Nagai, Issei Komuro
    Nature communications 10 (1) 2824 - 2824 2019/06 [Refereed][Not invited]
    The fibrogenic response in tissue-resident fibroblasts is determined by the balance between activation and repression signals from the tissue microenvironment. While the molecular pathways by which transforming growth factor-1 (TGF-β1) activates pro-fibrogenic mechanisms have been extensively studied and are recognized critical during fibrosis development, the factors regulating TGF-β1 signaling are poorly understood. Here we show that macrophage hypoxia signaling suppresses excessive fibrosis in a heart via oncostatin-m (OSM) secretion. During cardiac remodeling, Ly6Chi monocytes/macrophages accumulate in hypoxic areas through a hypoxia-inducible factor (HIF)-1α dependent manner and suppresses cardiac fibroblast activation. As an underlying molecular mechanism, we identify OSM, part of the interleukin 6 cytokine family, as a HIF-1α target gene, which directly inhibits the TGF-β1 mediated activation of cardiac fibroblasts through extracellular signal-regulated kinase 1/2-dependent phosphorylation of the SMAD linker region. These results demonstrate that macrophage hypoxia signaling regulates fibroblast activation through OSM secretion in vivo.
  • Masaya Sakamoto, Daisuke Matsutani, Soichiro Minato, Yuki Tsujimoto, Yosuke Kayama, Norihiko Takeda, Seiichi Ichikawa, Ryuzo Horiuchi, Kazunori Utsunomiya, Masako Nishikawa
    Diabetes care 42 (5) 816 - 823 2019/05 [Refereed][Not invited]
    OBJECTIVE: Precise monthly achievement rates for reaching guideline targets for HbA1c, blood pressure (BP), and lipid levels remain unknown. We evaluated achievement rates on a monthly basis in persons with type 2 diabetes mellitus (T2DM) and explored related factors. RESEARCH DESIGN AND METHODS: This retrospective study initially analyzed data on 104,601 persons with T2DM throughout Japan. Patients whose HbA1c, BP, and LDL cholesterol were measured ≥12 times during a 24-month period were included. We evaluated monthly achievement rates. Achieved targets were defined as HbA1c <7%, BP <130/80 mmHg, and LDL cholesterol <100 mg/dL. Achievement of all targets was expressed as the "all ABC achievement." RESULTS: A total of 4,678 patients were analyzed. The achievement rates of all ABC, HbA1c, BP, and LDL cholesterol were lowest in winter, with those for systolic BP (SBP) being particularly low (all ABC, summer 15.6%, winter 9.6%; HbA1c, 53.1%, 48.9%; SBP, 56.6%, 40.9%; LDL cholesterol, 50.8%, 47.2%). In winter, age ≥65 years (odds ratio 0.47 [95% CI 0.34-0.63]) was independently related to decreased achievement rates for SBP, BMI ≥25 kg/m2 (BMI 25-30 kg/m2, 0.45 [0.29-0.70]; BMI ≥30 kg/m2, 0.35 [0.22-0.57]), and diabetes duration ≥10 years (0.53 [0.37-0.76]) were independently related to lower achievement rates for HbA1c. Insulin use and sulfonylurea use were independently associated with the decreased all ABC achievement rates in both summer and winter. CONCLUSIONS: The all ABC achievement rate for guideline targets changed on a monthly basis. Seasonal variations in the all ABC achievement rate should be considered when managing T2DM in ordinary clinical practices.
  • Shun Minatsuki, Norihiko Takeda, Katsura Soma, Manami Katoh, Hisataka Maki, Masaru Hatano, Eiki Takimoto, Ichiro Manabe, Issei Komuro
    International heart journal 60 (2) 451 - 456 1349-2365 2019/03 [Refereed][Not invited]
    Chronic thromboembolic pulmonary hypertension (CTEPH) develops as a consequence of unresolved pulmonary embolism or clots in the pulmonary arteries. The obstruction not only reduces the area of the pulmonary vascular bed, but also elicits high pressure and high shear stress in the spared unobstructed arteries. Subsequent overflow of the small pulmonary arteries induces vascular remodeling, termed as overflow vasculopathy (OV). While the development of OV significantly contributes to the occurrence of pulmonary hypertension, its precise molecular mechanisms are yet to be determined.We established a novel murine pulmonary artery OV (PAOV) model, in which we resected left lung and induced redistribution of the cardiac output to the remaining pulmonary artery of the right lung. At 21 days after operation, mice showed an increase in the vascular media area, indicating the development of pulmonary arterial remodeling. In addition, right ventricular hypertrophy was detected in the PAOV model. Intriguingly, marked accumulation of F4/80-positive monocytes/macrophages was visualized in high-flow arteries, implying the role of an inflammatory process in the pathogenesis of overflow-induced vascular remodeling.
  • Asuka Kumagai, Kenji Shimizu, Riho Kurata, Xiaofeng Cui, Takayuki Isagawa, Masamitsu Harada, Jun Nagai, Yasuhiro Yoshida, Kei-Ichi Ozaki, Norihiko Takeda, Hiroaki Semba, Tomo Yonezawa
    Current pharmaceutical biotechnology 20 (1) 47 - 55 1389-2010 2019 [Refereed][Not invited]
    BACKGROUND: The immunotherapies against cancer, autoinmmune diseases or infection are remarkable development. These days programmed cell death (PD)-1 antibody-induced immune checkpoint blockade or chimeric antigen receptor-T cells (CAR-T) have been shown to have eminent therapeutic effects on tumor development. We have focused on adoptive transfer with human gamma delta T cells for novel immunotherapies. Additionally, IL-18 is one of the cytokines that enhances cytokine secretion and cytotoxicity of human gamma delta T cells. METHOD: Thus, we established novel cell lines stably expressing and secreting various types of human recombinant IL-18 proteins to their culture supernatants using episomal vector. We also differentiated primary cultured human gamma delta T cells from peripheral blood mononuclear leukocytes to validate biological activity of the IL-18 proteins using measuring IFN-γ by ELISA. RESULTS AND CONCLUSION: Finally, we demonstrated that the supernatant could activate human gamma delta T cells using monitoring interferon gamma in culture medium.
  • Hiroaki Fuji, Saori Ohmae, Naruto Noma, Masatoshi Takeiri, Hideto Yasutomi, Kazuya Izumi, Moe Ito, Masayasu Toyomoto, Soichiro Iwaki, Kenji Takemoto, Satoru Seo, Kojiro Taura, Shigeaki Hida, Mineyoshi Aoyama, Yasushi Ishihama, Masatoshi Hagiwara, Norihiko Takeda, Etsuro Hatano, Keiko Iwaisako, Shinji Uemoto, Masataka Asagiri
    Biochemical and biophysical research communications 503 (2) 544 - 549 0006-291X 2018/09 [Refereed][Not invited]
    Osteoclasts play a crucial role in osteolytic bone diseases, such as osteoporosis, rheumatoid arthritis, periodontitis, Paget's disease of bone and bone metastatic tumors. Therefore, controlling osteoclast differentiation and function has been considered a promising therapeutic strategy. Here, we show that necrostatin (Nec)-7, an inhibitor of programmed necrosis, strongly suppressed receptor activator of nuclear factor (NF)-κB ligand (RANKL)-induced osteoclastogenesis and bone resorption, without compromising macrophage colony-stimulating factor (M-CSF)-supported survival and growth of osteoclast precursor cells. Accordingly, Nec-7 significantly decreased the levels of RANKL-induced osteoclastogenic marker genes, such as cathepsin K. Mechanistically, Nec-7 neither affected MAPK nor NF-κB activation; however, it strongly inhibited the RANKL receptor (RANK) to nuclear factor of activated T cells c1 (NFATc1) signaling. Lentiviral expression of RANK in bone marrow-derived macrophages significantly restored osteoclastogenesis and NFATc1 amplification in Nec-7-treated cells. In this study, we revealed that Nec-7-sensitive pathways are crucially involved in osteoclast formation and function. Investigation of the molecular mechanism(s) through which Nec-7 inhibits RANK-NFATc1 signaling axis may lead to the development of new therapeutic strategies for bone disease.
  • Kana Kubota, Katsura Soma, Masae Uehara, Toshiro Inaba, Akihito Saito, Norihiko Takeda, Masaru Hatano, Hiroyuki Morita, Ryo Inuzuka, Yasutaka Hirata, Atsushi Yao, Issei Komuro
    International heart journal 59 (4) 877 - 880 1349-2365 2018/07 [Refereed][Not invited]
    Candida prosthetic endocarditis (CPE) is an uncommon and fatal complication in adults with congenital heart disease. The current guidelines for the management of fungal endocarditis recommend a combination of surgical and medical therapy. However, it still remains uncertain when surgical management in CPE patients should be performed. Therefore, the prognosis of CPE patients is very poor. Here we report a case of CPE in a 31-year-old woman who had undergone surgical repair for tetralogy of Fallot during childhood and pulmonary valve replacement at the age of 21 years. She underwent re-pulmonary valve replacement after being sufficiently sterilized with a 5-week course of antifungal medical therapy, leading to clinical improvement. In CPE patients, it is necessary to perform surgical therapy while suppressing the activity of fungi as much as possible.
  • Daisuke Matsutani, Masaya Sakamoto, Soichiro Minato, Yosuke Kayama, Norihiko Takeda, Ryuzo Horiuchi, Kazunori Utsunomiya
    Cardiovascular diabetology 17 (1) 100 - 100 2018/07 [Refereed][Not invited]
    BACKGROUND: The relationship between long-term glycemic variability (GV) represented by visit-to-visit HbA1c variability and baroreflex sensitivity (BRS) in type 2 diabetes mellitus (T2DM) has not been clarified by previous literature. The present study is the first to examine the relationships between visit-to-visit HbA1c variability and BRS. METHODS: This retrospective study initially analyzed data on 94 patients with T2DM. Visit-to-visit HbA1c variability was evaluated using the intrapersonal coefficient of variation (CV), standard deviation (SD), and adjusted SD of 8 or more serial measurements of HbA1c during a 2-year period. The BRS was analyzed using the sequence method. Short-term GV was assessed by measuring the glucose CV during 24-h continuous glucose monitoring (CGM). The primary objective was to determine if there was a relationship between visit-to-visit HbA1c variability (HbA1c CV) and BRS. Secondary objectives were to examine the relationship between other variables and BRS and the respective and combined effects of long-term GV (HbA1c CV) and short-term GV (CGM CV) on BRS. RESULTS: A total of 57 patients (mean age 67.2 ± 7.7 years, mean HbA1c 7.3 ± 1.0%) who met this study's inclusion criteria were finally analyzed. In the univariate analysis, HbA1c CV (r = - 0.354, p = 0.007), HbA1c SD (r = - 0.384, p = 0.003), and adjusted HbA1c SD (r = - 0.391, p = 0.003) were significantly related to low levels of BRS. Multiple regression analysis showed that HbA1c CV, HbA1c SD, and adjusted HbA1c SD were inversely related to BRS. Furthermore, although the increase in either long-term GV (HbA1c CV) or short-term GV (CGM CV) as determined by 24-h CGM was inversely correlated with BRS, additional reductions in BRS were not shown in participants with both HbA1c CV and CGM CV values above the median. CONCLUSIONS: Visit-to-visit HbA1c variability was inversely related to BRS independently of the mean HbA1c in patients with T2DM. Therefore, visit-to-visit HbA1c variability might be a marker of reduced BRS in T2DM.
  • Leona Matsumoto, Yasushi Hirota, Tomoko Saito-Fujita, Norihiko Takeda, Tomoki Tanaka, Takehiro Hiraoka, Shun Akaeda, Hidetoshi Fujita, Ryoko Shimizu-Hirota, Shota Igaue, Mitsunori Matsuo, Hirofumi Haraguchi, Mayuko Saito-Kanatani, Tomoyuki Fujii, Yutaka Osuga
    The Journal of clinical investigation 128 (7) 3186 - 3197 0021-9738 2018/07 [Refereed][Not invited]
    Although it has been reported that hypoxia inducible factor 2 α (Hif2a), a major transcriptional factor inducible by low oxygen tension, is expressed in the mouse uterus during embryo implantation, its role in pregnancy outcomes remains unclear. This study aimed to clarify functions of uterine HIF using transgenic mouse models. Mice with deletion of Hif2a in the whole uterus (Hif2a-uKO mice) showed infertility due to implantation failure. Supplementation with progesterone (P4) and leukemia inhibitory factor (LIF) restored decidual growth arrest and aberrant position of implantation sites in Hif2a-uKO mice, respectively, but did not rescue pregnancy failure. Histological analyses in Hif2a-uKO mice revealed persistence of the intact luminal epithelium, which blocked direct contact between stroma and embryo, inactivation of PI3K-AKT pathway (embryonic survival signal), and failed embryo invasion. Mice with stromal deletion of Hif2a (Hif2a-sKO mice) showed infertility with impaired embryo invasion and those with epithelial deletion of Hif2a (Hif2a-eKO mice) showed normal fertility, suggesting the importance of stromal HIF2α in embryo invasion. This was reflected in reduced expression of membrane type 2 metalloproteinase (MT2-MMP), lysyl oxidase (LOX), VEGF, and adrenomedullin (ADM) in Hif2a-uKO stroma at the attachment site, suggesting that stromal HIF2α regulates these mediators to support blastocyst invasion. These findings provide new insight that stromal HIF2α allows trophoblast invasion through detachment of the luminal epithelium and activation of an embryonic survival signal.
  • Daisuke Matsutani, Masaya Sakamoto, Yosuke Kayama, Norihiko Takeda, Ryuzo Horiuchi, Kazunori Utsunomiya
    Cardiovascular diabetology 17 (1) 73 - 73 1475-2840 2018/05 [Refereed][Not invited]
    BACKGROUND: Type 2 diabetes mellitus (T2DM) greatly increases the risks of cardiovascular disease and heart failure. In particular, left ventricular diastolic dysfunction that develops from the early stages of T2DM is an important factor in the onset and exacerbation of heart failure. The effect of sodium-glucose cotransporter 2 inhibitors on left ventricular diastolic function has not been elucidated. We have performed the first prospective study on the effects of canagliflozin on left ventricular diastolic function in T2DM. METHODS: This study was performed to evaluate the effects of additional treatment with canagliflozin for 3 months on left ventricular diastolic function in patients with T2DM. A total of 38 patients with T2DM were consecutively recruited for this study. Left ventricular diastolic function was assessed by echocardiography. The primary study outcome was a change in the septal E/e' as a parameter of left ventricular diastolic function. RESULTS: A total of 37 patients (25 males and 12 females) were included in the analysis. Mean age of participants was 64.2 ± 8.1 years (mean ± SD), mean duration of diabetes was 13.5 ± 8.1 years, and mean HbA1c was 7.9 ± 0.7%. Of the participants, 86.5% had hypertension, 100% had dyslipidemia, and 32.4% had cardiovascular disease. Canagliflozin significantly improved left ventricular diastolic function (septal E/e' ratio 13.7 ± 3.5-12.1 ± 2.8, p = 0.001). Furthermore, among the various parameters that changed through the administration of canagliflozin, only changes in hemoglobin significantly correlated with changes in the septal E/e' ratio (p = 0.002). In multiple regression analysis, changes in hemoglobin were also revealed to be an independent predictive factor for changes in the septal E/e' ratio. CONCLUSIONS: This study showed for the first time that canagliflozin could improve left ventricular diastolic function within 3 months in patients with T2DM. The benefit was especially apparent in patients with substantially improved hemoglobin values. Trial registration UMIN Clinical Trials Registry UMIN000028141.
  • Ryo Yonashiro, Kayoko Eguchi, Masaki Wake, Norihiko Takeda, Koh Nakayama
    Cancer research 78 (7) 1592 - 1603 0008-5472 2018/04 [Refereed][Not invited]
    Downregulation of pyruvate dehydrogenase (PDH) is critical for the aberrant preferential activation of glycolysis in cancer cells under normoxic conditions. Phosphorylation-dependent inhibition of PDH is a relevant event in this process, but it is not durable as it relies on PDH kinases that are activated ordinarily under hypoxic conditions. Thus, it remains unclear how PDH is durably downregulated in cancer cells that are not hypoxic. Building on evidence that PDH activity depends on the stability of a multi-protein PDH complex, we found that the PDH-E1β subunit of the PDH complex is downregulated to inhibit PDH activity under conditions of prolonged hypoxia. After restoration of normoxic conditions, reduced expression of PDH-E1β was sustained such that glycolysis remained highly activated. Notably, PDH-E1β silencing in cancer cells produced a metabolic state strongly resembling the Warburg effect, but inhibited tumor growth. Conversely, enforced exogenous expression of PDH-E1β durably increased PDH activity and promoted the malignant growth of breast cancer cells in vivo Taken together, our results establish the specific mechanism through which PDH acts as an oncogenic factor by tuning glycolytic metabolism in cancer cells.Significance: This seminal study offers a mechanistic explanation for why glycolysis is aberrantly activated in normoxic cancer cells, offering insights into this long-standing hallmark of cancer termed the Warburg effect. Cancer Res; 78(7); 1592-603. ©2018 AACR.
  • Yu Nakagama, Ryo Inuzuka, Kayoko Ichimura, Munetoshi Hinata, Hiroki Takehara, Norihiko Takeda, Satsuki Kakiuchi, Kazuhiro Shiraga, Hiroko Asakai, Takahiro Shindo, Yoichiro Hirata, Makiko Saitoh, Akira Oka
    Circulation. Heart failure 11 (4) e004660  1941-3289 2018/04 [Refereed][Not invited]
  • Daisuke Matsutani, Masaya Sakamoto, Hiroyuki Iuchi, Souichirou Minato, Hirofumi Suzuki, Yosuke Kayama, Norihiko Takeda, Ryuzo Horiuchi, Kazunori Utsunomiya
    Cardiovascular diabetology 17 (1) 36 - 36 1475-2840 2018/03 [Refereed][Not invited]
    BACKGROUND: It is presently unclear whether glycemic variability (GV) is associated with baroreflex sensitivity (BRS), which is an early indicator of cardiovascular autonomic neuropathy. The present study is the first to examine the relationships between BRS and GV measured using continuous glucose monitoring (CGM). METHODS: This was a multicenter, prospective, open-label clinical trial. A total of 102 patients with type 2 diabetes were consecutively recruited for this study. GV was assessed by measuring the standard deviation (SD), glucose coefficient of variation (CV), and the mean amplitude of glycemic excursions (MAGE) during CGM. The BRS was analyzed from electrocardiogram and blood pressure recordings using the sequence method on the first day of hospitalization. RESULTS: A total of 94 patients (mean diabetes duration 9.7 ± 9.6 years, mean HbA1c 61.0 ± 16.8 mmol/mol [7.7 ± 1.5%]) were analyzed. In the univariate analysis, CGM-SD (r = - 0.375, p = 0.000), CGM-CV (r = - 0.386, p = 0.000), and MAGE (r = - 0.395, p = 0.000) were inversely related to BRS. In addition to GV, the level of BRS correlated with the coefficient of variation in the R-R intervals (CVR-R) (r = 0.520, p = 0.000), heart rate (HR) (r = - 0.310, p = 0.002), cardio-ankle vascular index (CAVI) (r = - 0.326, p = 0.001), age (r = - 0.519, p = 0.000), and estimated glomerular filtration rate (eGFR) (r = 0.276, p = 0.007). Multiple regression analysis showed that CGM-CV and MAGE were significantly related to a decrease in BRS. These findings remained after adjusting the BRS for age, sex, hypertension, dyslipidemia, HR, eGFR, CAVI, and CGM-mean glucose. Additionally, BRS was divided according to quartiles of the duration of diabetes (Q1-4). BRS decreased after a 2-year duration of diabetes independently of age and sex. CONCLUSIONS: GV was inversely related to BRS independently of blood glucose levels in type 2 diabetic patients. Measurement of BRS may have the potential to predict CV events in consideration of GV. Trial registration UMIN Clinical Trials Registry UMIN000025964, 28/02/2017.
  • Justin Goodwin, Hyunsung Choi, Meng-Hsiung Hsieh, Michael L Neugent, Jung-Mo Ahn, Heather N Hayenga, Pankaj K Singh, David B Shackelford, In-Kyu Lee, Vladimir Shulaev, Shanta Dhar, Norihiko Takeda, Jung-Whan Kim
    American journal of respiratory cell and molecular biology 58 (2) 216 - 231 1044-1549 2018/02 [Refereed][Not invited]
    Hypoxia has long been implicated in the pathogenesis of fibrotic diseases. Aberrantly activated myofibroblasts are the primary pathological driver of fibrotic progression, yet how various microenvironmental influences, such as hypoxia, contribute to their sustained activation and differentiation is poorly understood. As a defining feature of hypoxia is its impact on cellular metabolism, we sought to investigate how hypoxia-induced metabolic reprogramming affects myofibroblast differentiation and fibrotic progression, and to test the preclinical efficacy of targeting glycolytic metabolism for the treatment of pulmonary fibrosis. Bleomycin-induced pulmonary fibrotic progression was evaluated in two independent, fibroblast-specific, promoter-driven, hypoxia-inducible factor (Hif) 1A knockout mouse models and in glycolytic inhibitor, dichloroacetate-treated mice. Genetic and pharmacological approaches were used to explicate the role of metabolic reprogramming in myofibroblast differentiation. Hypoxia significantly enhanced transforming growth factor-β-induced myofibroblast differentiation through HIF-1α, whereas overexpression of the critical HIF-1α-mediated glycolytic switch, pyruvate dehydrogenase kinase 1 (PDK1) was sufficient to activate glycolysis and potentiate myofibroblast differentiation, even in the absence of HIF-1α. Inhibition of the HIF-1α/PDK1 axis by genomic deletion of Hif1A or pharmacological inhibition of PDK1 significantly attenuated bleomycin-induced pulmonary fibrosis. Our findings suggest that HIF-1α/PDK1-mediated glycolytic reprogramming is a critical metabolic alteration that acts to promote myofibroblast differentiation and fibrotic progression, and demonstrate that targeting glycolytic metabolism may prove to be a potential therapeutic strategy for the treatment of pulmonary fibrosis.
  • Hajime Abe, Nobuo Iguchi, Yuko Utanohara, Kaori Takada, Yasuki Hen, Haruhiko Machida, Norihiko Takeda, Tetsuya Sumiyoshi
    International heart journal 59 (1) 77 - 80 1349-2365 2018/01 [Refereed][Not invited]
    Manual planimetry is a well-established method using transesophageal echocardiography (TEE) to assess the severity of aortic stenosis (AS). TEE, however, is a less than optimal approach in patients with calcified valves. Even when using cine-cardiac magnetic resonance (CMR), it is often difficult to evaluate the true border of the aortic orifice because of jet turbulence. With phase-contrast sequences of CMR, high flow signals at the aortic orifice can be clearly visualized, even in cases with severe calcification and jet turbulence. Therefore, the aims of the present study were to compare the utility of CMR using phase-contrast imaging with TEE and cine-CMR for the performance of planimetry of the aortic valve. The study cohort consisted of 30 consecutive patients with moderate or severe aortic valve stenosis documented by TEE who had undergone phase-contrast and cine-CMR for the evaluation of AS. Manual planimetry of the area of high flow signal was traced over the phase-contrast images at systolic peak, when the aortic valve is maximally opened. The results showed that the aortic valvular area (AVA) value derived from TEE correlated better with phase-contrast planimetry (r2 = 0.84, P < 0.05) than cine-mode planimetry (r2 = 0.57, P < 0.05). Bland-Altman plots indicated that the variation of measuring AVA was greater using the cine-mode method than the phase-contrast method. In conclusion, phase-contrast CMR offers a tool for evaluating the severity of aortic valve stenosis noninvasively. Phase-contrast CMR has the potential to become a routine clinical option as an alternative to TEE, at least in selected cases.
  • Yu Ishimoto, Reiko Inagi, Daisuke Yoshihara, Masanori Kugita, Shizuko Nagao, Akira Shimizu, Norihiko Takeda, Masaki Wake, Kenjiro Honda, Jing Zhou, Masaomi Nangaku
    Molecular and cellular biology 37 (24) 0270-7306 2017/12 [Refereed][Not invited]
    Autosomal dominant polycystic kidney disease (ADPKD) constitutes the most inherited kidney disease. Mutations in the PKD1 and PKD2 genes, encoding the polycystin 1 and polycystin 2 Ca2+ ion channels, respectively, result in tubular epithelial cell-derived renal cysts. Recent clinical studies demonstrate oxidative stress to be present early in ADPKD. Mitochondria comprise the primary reactive oxygen species source and also their main effector target; however, the pathophysiological role of mitochondria in ADPKD remains uncharacterized. To clarify this function, we examined the mitochondria of cyst-lining cells in ADPKD model mice (Ksp-Cre PKD1flox/flox) and rats (Han:SPRD Cy/+), demonstrating obvious tubular cell morphological abnormalities. Notably, the mitochondrial DNA copy number and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) expression were decreased in ADPKD model animal kidneys, with PGC-1α expression inversely correlated with oxidative stress levels. Consistent with these findings, human ADPKD cyst-derived cells with heterozygous and homozygous PKD1 mutation exhibited morphological and functional abnormalities, including increased mitochondrial superoxide. Furthermore, PGC-1α expression was suppressed by decreased intracellular Ca2+ levels via calcineurin, p38 mitogen-activated protein kinase (MAPK), and nitric oxide synthase deactivation. Moreover, the mitochondrion-specific antioxidant MitoQuinone (MitoQ) reduced intracellular superoxide and inhibited cyst epithelial cell proliferation through extracellular signal-related kinase/MAPK inactivation. Collectively, these results indicate that mitochondrial abnormalities facilitate cyst formation in ADPKD.
  • シン・メタボリズム〜代謝が関わる多彩な生命現象〜 老化・がん化耐性齧歯類ハダカデバネズミのエネルギー代謝を制御する分子機構の解析
    岡 香織, 大岩 祐基, 河村 佳見, 杉浦 悠毅, 南嶋 洋司, 末松 誠, 和氣 正樹, 武田 憲彦, 城戸 康年, 稲岡 健ダニエル, 北 潔, 三浦 恭子
    生命科学系学会合同年次大会 生命科学系学会合同年次大会運営事務局 2017年度 [2PW05 - 4] 2017/12
  • Hiroyuki Iuchi, Masaya Sakamoto, Daisuke Matsutani, Hirofumi Suzuki, Yosuke Kayama, Norihiko Takeda, Kazunori Utsunomiya
    Blood pressure monitoring 22 (6) 351 - 354 1359-5237 2017/12 [Refereed][Not invited]
    It remains unclear whether ambulatory blood pressure variability (BPV) contributes toward day-by-day BPV, despite the fact that not only day-by-day but also ambulatory BPV is reported to be a risk factor for type 2 diabetes patients. This study aimed to determine the association between day-by-day BPV and ambulatory BPV, which is especially distinguished between diurnal and nocturnal BPV, in type 2 diabetes patients. Day-by-day and ambulatory BPV were assessed in 30 type 2 diabetes patients (aged 54±15 years; 87% men; glycated hemoglobin: 9.1±1.9%) in inpatient settings. Day-by-day systolic BPV was correlated significantly with diurnal systolic BPV (r=0.426, P=0.019), but not nocturnal systolic BPV (r=0.175, P=0.354). Multiple regression analysis showed that diurnal systolic BPV and diurnal mean systolic blood pressure were associated independently with day-by-day systolic BPV. With respect to type 2 diabetes, these findings suggest that day-by-day BPV is reflected in diurnal BPV rather than nocturnal BPV.
  • Ewelina Krzywinska, Chahrazade Kantari-Mimoun, Yann Kerdiles, Michal Sobecki, Takayuki Isagawa, Dagmar Gotthardt, Magali Castells, Johannes Haubold, Corinne Millien, Thomas Viel, Bertrand Tavitian, Norihiko Takeda, Joachim Fandrey, Eric Vivier, Veronika Sexl, Christian Stockmann
    Nature communications 8 (1) 1597 - 1597 2041-1723 2017/11 [Refereed][Not invited]
    Productive angiogenesis, a prerequisite for tumour growth, depends on the balanced release of angiogenic and angiostatic factors by different cell types within hypoxic tumours. Natural killer (NK) cells kill cancer cells and infiltrate hypoxic tumour areas. Cellular adaptation to low oxygen is mediated by Hypoxia-inducible factors (HIFs). We found that deletion of HIF-1α in NK cells inhibited tumour growth despite impaired tumour cell killing. Tumours developing in these conditions were characterised by a high-density network of immature vessels, severe haemorrhage, increased hypoxia, and facilitated metastasis due to non-productive angiogenesis. Loss of HIF-1α in NK cells increased the bioavailability of the major angiogenic cytokine vascular endothelial growth factor (VEGF) by decreasing the infiltration of NK cells that express angiostatic soluble VEGFR-1. In summary, this identifies the hypoxic response in NK cells as an inhibitor of VEGF-driven angiogenesis, yet, this promotes tumour growth by allowing the formation of functionally improved vessels.
  • Manami Katoh, Norihiko Takeda, Takahide Arimoto, Hajime Abe, Katsutoshi Oda, Yutaka Osuga, Tomoyuki Fujii, Issei Komuro
    International heart journal 58 (5) 803 - 805 1349-2365 2017/10 [Refereed][Not invited]
    Bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF)-A, is currently used to treat patients with ovarian or colon cancer. While several cardiovascular toxicities related to bevacizumab-containing regimens have been reported, the effect of bevacizumab on the coronary microcirculation has not been fully elucidated. Here we report a case of 54-year-old female patient who developed microvascular angina after a series of bevacizumab-containing chemotherapeutic regimen. The discontinuation of bevacizumab and nicorandil administration was effective in alleviating her chest discomfort and the ischemic changes on her ECG. This highlights the possibility that coronary microvascular angina can be induced in patients treated with bevacizumab-containing chemotherapy. It should also be noted that nicorandil can be effective in managing microvascular angina.
  • Hiroyuki Iuchi, Masaya Sakamoto, Daisuke Matsutani, Hirofumi Suzuki, Yosuke Kayama, Norihiko Takeda, Susumu Minamisawa, Kazunori Utsunomiya
    Scientific reports 7 (1) 11906 - 11906 2045-2322 2017/09 [Refereed][Not invited]
    Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral antidiabetic drugs that promote urinary glucose excretion. Conversely, they cause behavioural changes, such as hyperphagia, that result in a positive energy balance. The relationship between energy homeostasis and SGLT2 inhibitors-induced behavioural changes remains unclear. Here we show that ipragliflozin, a SGLT2 inhibitor, time-dependently affects behaviour and enhances energy expenditure in normal and type 2 diabetic Goto-Kakizaki (GK) rats, using continuous glucose telemetry. Alongside increased urinary glucose excretion, ipragliflozin increased total food and water intakes in normal and GK rats. In normal rats, ipragliflozin treatment acutely disturbed the circadian rhythms of food and water intakes, activity, and body temperature. Subsequently, these rhythms gradually returned towards a normal state. However, activity and body temperature remained suppressed. In GK rats, ipragliflozin did not affect circadian rhythms. Blood glucose values assessed by glucose telemetry were significantly reduced in both ipragliflozin-treated groups. Despite these behavioural and glycaemic changes, ipragliflozin significantly increased oxygen consumption during dark and light periods in both groups. Ipragliflozin reduced body weight in normal rats only. Thus, ipragliflozin decreases blood glucose beyond compensatory hyperphagia in normal and GK rats, resulting in enhanced basal energy expenditure, despite acutely altering circadian rhythms in normoglycaemic individuals.
  • Hajime Abe, Hiroaki Semba, Norihiko Takeda
    Journal of atherosclerosis and thrombosis 24 (9) 884 - 894 1340-3478 2017/09 [Refereed][Not invited]
    The circulatory system distributes blood flow to each tissue and transports oxygen and nutrients. Peripheral circulation is required to maintain the physiological function in each tissue. Disturbance of circulation, therefore, decreases oxygen delivery, leading to tissue hypoxia which takes place in several cardiovascular disorders including atherosclerosis, pulmonary arterial hypertension and heart failure. While tissue hypoxia can be induced because of cardiovascular disorders, hypoxia signaling itself has a potential to modulate tissue remodeling processes or the severity of the cardiovascular disorders. Hypoxia inducible factor-1α (HIF-1α) and HIF-2α belongs to a group of transcription factors which mediate most of the cellular responses to hypoxia at a transcriptional level. We, and others, have reported that HIF-α signaling plays a critical role in the initiation or the regulation of inflammation. HIF-α signaling contributes to the tissue remodeling processes; thus it has a potential to become a therapeutic target. Elucidation of the molecular link, therefore, between hypoxia signaling and tissue remodeling will greatly help us to understand the pathophysiology of the cardiovascular disorders. The purpose of this review is to give a brief overview of the current understanding about the function HIF-α in inflammation processes especially by focusing on its roles in macrophages. In addition, the pathophysiological roles of hypoxia signaling for the development of cardiovascular disease will be discussed.
  • Justin Goodwin, Michael L Neugent, Shin Yup Lee, Joshua H Choe, Hyunsung Choi, Dana M R Jenkins, Robin J Ruthenborg, Maddox W Robinson, Ji Yun Jeong, Masaki Wake, Hajime Abe, Norihiko Takeda, Hiroko Endo, Masahiro Inoue, Zhenyu Xuan, Hyuntae Yoo, Min Chen, Jung-Mo Ahn, John D Minna, Kristi L Helke, Pankaj K Singh, David B Shackelford, Jung-Whan Kim
    Nature communications 8 15503 - 15503 2041-1723 2017/05 [Refereed][Not invited]
    Adenocarcinoma (ADC) and squamous cell carcinoma (SqCC) are the two predominant subtypes of non-small cell lung cancer (NSCLC) and are distinct in their histological, molecular and clinical presentation. However, metabolic signatures specific to individual NSCLC subtypes remain unknown. Here, we perform an integrative analysis of human NSCLC tumour samples, patient-derived xenografts, murine model of NSCLC, NSCLC cell lines and The Cancer Genome Atlas (TCGA) and reveal a markedly elevated expression of the GLUT1 glucose transporter in lung SqCC, which augments glucose uptake and glycolytic flux. We show that a critical reliance on glycolysis renders lung SqCC vulnerable to glycolytic inhibition, while lung ADC exhibits significant glucose independence. Clinically, elevated GLUT1-mediated glycolysis in lung SqCC strongly correlates with high 18F-FDG uptake and poor prognosis. This previously undescribed metabolic heterogeneity of NSCLC subtypes implicates significant potential for the development of diagnostic, prognostic and targeted therapeutic strategies for lung SqCC, a cancer for which existing therapeutic options are clinically insufficient.
  • Saori Ohmae, Naruto Noma, Masayasu Toyomoto, Masahiro Shinohara, Masatoshi Takeiri, Hiroaki Fuji, Kenji Takemoto, Keiko Iwaisako, Tomoko Fujita, Norihiko Takeda, Makoto Kawatani, Mineyoshi Aoyama, Masatoshi Hagiwara, Yasushi Ishihama, Masataka Asagiri
    Scientific reports 7 41710 - 41710 2045-2322 2017/03 [Refereed][Not invited]
    Osteoclasts degrade bone matrix proteins via the secretion of lysosomal enzymes. However, the precise mechanisms by which lysosomal components are transported and fused to the bone-apposed plasma membrane, termed ruffled border membrane, remain elusive. Here, we identified coronin 1A as a negative regulator of exocytotic release of cathepsin K, one of the most important bone-degrading enzymes in osteoclasts. The modulation of coronin 1A expression did not alter osteoclast differentiation and extracellular acidification, but strongly affected the secretion of cathepsin K and osteoclast bone-resorption activity, suggesting the coronin 1A-mediated regulation of lysosomal trafficking and protease exocytosis. Further analyses suggested that coronin 1A prevented the lipidation-mediated sorting of the autophagy-related protein LC3 to the ruffled border and attenuated lysosome-plasma membrane fusion. In this process, the interactions between coronin 1A and actin were crucial. Collectively, our findings indicate that coronin 1A is a pivotal component that regulates lysosomal fusion and the secretion pathway in osteoclast-lineage cells and may provide a novel therapeutic target for bone diseases.
  • Jun Matsuda, Katsuhito Fujiu, Solji Roh, Miyu Tajima, Hisataka Maki, Toshiya Kojima, Tetsuo Ushiku, Kan Nawata, Norihiko Takeda, Masafumi Watanabe, Hiroshi Akazawa, Issei Komuro
    International heart journal 58 (1) 140 - 143 1349-2365 2017/02 [Refereed][Not invited]
    Cardiac involvement in systemic sarcoidosis sometimes provokes life-threatening ventricular tachyarrhythmia. Steroid administration is one of the fundamental anti-arrhythmia therapies. For an indication of steroid therapy, a definitive diagnosis of sarcoidosis is required.1) However, cases that are clearly suspected of cardiac sarcoidosis based on their clinical courses sometimes do not meet the current diagnostic criteria and result in the loss of an appropriate opportunity to perform steroid therapy.Here we report a case that was diagnosed as sarcoidosis by incidental biopsy of an inguinal lymph node during cardiac resuscitation for cardiac tamponade.2) While the inguinal lymph node was not swollen on computed tomography, a specimen obtained from an incidental biopsy during the exposure of a femoral vessel for the establishment of extracorporeal cardio-pulmonary resuscitation showed a non-caseating granuloma.This findings suggest a non-swelling lymph node biopsy might be an alternative strategy for the diagnosis for sarcoidosis if other standard strategies do not result in a diagnosis of sarcoidosis.
  • Haruka Chino, Yosuke Amano, Yasuhiro Yamauchi, Jun Matsuda, Norihiko Takeda, Goh Tanaka, Daiya Takai, Takahide Nagase
    JOURNAL OF THORACIC DISEASE 8 (9) 2646 - 2650 2072-1439 2016/09 [Refereed][Not invited]
    We report the case of a 55-year-old man with stage IV lung adenocarcinoma who received carboplatin-paclitaxel-bevacizumab chemotherapy as second-line therapy. After four cycles of chemotherapy, he experienced syncope with a decrease in blood pressure. Electrocardiography (ECG) revealed atrial fibrillation. Cardiac ultrasonography showed a markedly reduced ejection fraction (45%), with moderate decrease in comparison to that before chemotherapy (66%). Bisoprolol fumarate was initiated, and the conversion to sinus rhythm was detected by ECG 4 days after the syncope. At that time, no improvement in the ejection fraction was detected. Bevacizumab-associated cardiotoxicity was suspected, and bevacizumab maintenance therapy was discontinued, although the chemotherapy achieved a stable disease status based on the Response Evaluation Criteria in Solid Tumors. Two months after bevacizumab cessation, the ejection fraction improved to pretreatment level (62%). To the best of our knowledge, this is the first report on cardiogenic syncope due to left ventricular dysfunction that is most consistent with bevacizumab-associated cardiotoxicity in non-small cell lung cancer (NSCLC). Our results indicate that bevacizumab could lead to cardiotoxicity in patients with NSCLC and suggest the importance of the follow-up cardiac ultrasonography.
  • Norihiko Takeda, Koji Maemura
    HYPERTENSION RESEARCH 39 (6) 383 - 390 0916-9636 2016/06 [Refereed][Not invited]
    The onset of cardiovascular diseases often shows time-of-day variation. Acute myocardial infarction or ventricular arrhythmia such as ventricular tachycardia occurs mainly in the early morning. Multiple biochemical and physiological parameters show circadian rhythm, which may account for the diurnal variation of cardiovascular events. These include the variations in blood pressure, activity of the autonomic nervous system and renin-angiotensin axis, coagulation cascade, vascular tone and the intracellular metabolism of cardiomyocytes. Importantly, the molecular clock system seems to underlie the circadian variation of these parameters. The center of the biological clock, also known as the central clock, exists in the suprachiasmatic nucleus. In contrast, the molecular clock system is also activated in each cell of the peripheral organs and constitute the peripheral clock. The biological clock system is currently considered to have a beneficial role in maintaining the homeostasis of each organ. Discoordination, however, between the peripheral clock and external environment could potentially underlie the development of cardiovascular events. Therefore, understanding the molecular and cellular pathways by which cardiovascular events occur in a diurnal oscillatory pattern will help the establishment of a novel therapeutic approach to the management of cardiovascular disorders.
  • Hiroaki Semba, Norihiko Takeda, Takayuki Isagawa, Yuki Sugiura, Kurara Honda, Masaki Wake, Hidenobu Miyazawa, Yoshifumi Yamaguchi, Masayuki Miura, Dana M. R. Jenkins, Hyunsung Choi, Jung-whan Kim, Masataka Asagiri, Andrew S. Cowburn, Hajime Abe, Katsura Soma, Katsuhiro Koyama, Manami Katoh, Keimon Sayama, Nobuhito Goda, Randall S. Johnson, Ichiro Manabe, Ryozo Nagai, Issei Komuro
    NATURE COMMUNICATIONS 7 11635  2041-1723 2016/05 [Refereed][Not invited]
    In severely hypoxic condition, HIF-1 alpha-mediated induction of Pdk1 was found to regulate glucose oxidation by preventing the entry of pyruvate into the tricarboxylic cycle. Monocyte-derived macrophages, however, encounter a gradual decrease in oxygen availability during its migration process in inflammatory areas. Here we show that HIF-1 alpha-PDK1-mediated metabolic changes occur in mild hypoxia, where mitochondrial cytochrome c oxidase activity is unimpaired, suggesting a mode of glycolytic reprogramming. In primary macrophages, PKM2, a glycolytic enzyme responsible for glycolytic ATP synthesis localizes in filopodia and lammelipodia, where ATP is rapidly consumed during actin remodelling processes. Remarkably, inhibition of glycolytic reprogramming with dichloroacetate significantly impairs macrophage migration in vitro and in vivo. Furthermore, inhibition of the macrophage HIF-1 alpha-PDK1 axis suppresses systemic inflammation, suggesting a potential therapeutic approach for regulating inflammatory processes. Our findings thus demonstrate that adaptive responses in glucose metabolism contribute to macrophage migratory activity.
  • Yasuo Mori, Nobuaki Takahashi, Onur Kerem Polat, Tatsuki Kurokawa, Norihiko Takeda, Masahiro Inoue
    PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY 468 (1) 85 - 97 0031-6768 2016/01 [Refereed][Not invited]
    Regulation of ion channels is central to the mechanisms that underlie immediate acute physiological responses to changes in the availability of molecular oxygen (O-2). A group of cation-permeable channels that are formed by transient receptor potential (TRP) proteins have been characterized as exquisite sensors of redox reactive species and as efficient actuators of electric/ionic signals in vivo. In this review, we first discuss how redox-sensitive TRP channels such as TRPA1 have recently emerged as sensors of the relatively inert oxidant O-2. With regard to the physiological significance of O-2 sensor TRP channels, vagal TRPA1 channels are mainly discussed with respect to their role in respiratory regulation in comparison with canonical pathways in glomus cells of the carotid body, which is a well-established O-2-sensing organ. TRPM7 channels are discussed regarding hypoxia-sensing function in ischemic cell death. Also, ubiquitous expression of TRPA1 and TRPM7 together with their physiological relevance in the body is examined. Finally, based upon these studies on TRP channels, we propose a hypothesis of "O-2 remodeling." The hypothesis is that cells detect deviation of O-2 availability from appropriate levels via sensors and adjust local O-2 environments in vivo by controlling supply and consumption of O-2 via pathways comprising cellular signals and transcription factors downstream of sensors, which consequently optimize physiological functions. This new insight into O-2 adaptation through ion channels, particularly TRPs, may foster a paradigm shift in our understanding in the biological significance of O-2.
  • Norihiko Takeda, Koji Maemura
    CELLULAR AND MOLECULAR LIFE SCIENCES 72 (17) 3225 - 3234 1420-682X 2015/09 [Refereed][Not invited]
    The time of onset of cardiovascular disorders such as myocardial infarctions or ventricular arrhythmias exhibits a circadian rhythm. Diurnal variations in autonomic nervous activity, plasma cortisol level or renin-angiotensin activity underlie the pathogenesis of cardiovascular diseases. Transcriptional-translational feedback loop of the clock genes constitute a molecular clock system. In addition to the central clock in the suprachiasmatic nucleus, clock genes are also expressed in a circadian fashion in each organ to make up the peripheral clock. The peripheral clock seems to be beneficial for anticipating external stimuli and thus contributes to the maintenance of organ homeostasis. Loss of synchronization between the central and peripheral clocks also augments disease progression. Moreover, accumulating evidence shows that clock genes affect inflammatory and intracellular metabolic signaling. Elucidating the roles of the molecular clock in cardiovascular pathology through the identification of clock controlled genes will help to establish a novel therapeutic approach for cardiovascular disorders.
  • Yutaka Tojo, Hiroki Sekine, Ikuo Hirano, Xiaoqing Pan, Tomokazu Souma, Tadayuki Tsujita, Shin-ichi Kawaguchi, Norihiko Takeda, Kotaro Takeda, Guo-Hua Fong, Takashi Dan, Masakazu Ichinose, Toshio Miyata, Masayuki Yamamoto, Norio Suzuki
    Molecular and cellular biology 35 (15) 2658 - 72 0270-7306 2015/08 [Refereed][Not invited]
    Erythropoietin (Epo) is produced in the kidney and liver in a hypoxia-inducible manner via the activation of hypoxia-inducible transcription factors (HIFs) to maintain oxygen homeostasis. Accelerating Epo production in hepatocytes is one plausible therapeutic strategy for treating anemia caused by kidney diseases. To elucidate the regulatory mechanisms of hepatic Epo production, we analyzed mouse lines harboring liver-specific deletions of genes encoding HIF-prolyl-hydroxylase isoforms (PHD1, PHD2, and PHD3) that mediate the inactivation of HIF1α and HIF2α under normal oxygen conditions. The loss of all PHD isoforms results in both polycythemia, which is caused by Epo overproduction, and fatty livers. We found that deleting any combination of two PHD isoforms induces polycythemia without steatosis complications, whereas the deletion of a single isoform induces no apparent phenotype. Polycythemia is prevented by the loss of either HIF2α or the hepatocyte-specific Epo gene enhancer (EpoHE). Chromatin analyses show that the histones around EpoHE dissociate from the nucleosome structure after HIF2α activation. HIF2α also induces the expression of HIF3α, which is involved in the attenuation of Epo production. These results demonstrate that the total amount of PHD activity is more important than the specific function of each isoform for hepatic Epo expression regulated by a PHD-HIF2α-EpoHE cascade in vivo.
  • Hajime Abe, Nobuo Iguchi, Yuko Utanohara, Kanki Inoue, Itaru Takamisawa, Atsushi Seki, Kouhei Tanizaki, Norihiko Takeda, Tetsuya Tohbaru, Ryuta Asano, Masatoshi Nagayama, Morimasa Takayama, Jun Umemura, Tetsuya Sumiyoshi, Hitonobu Tomoike
    INTERNATIONAL JOURNAL OF CARDIOLOGY 176 (3) 969 - 974 0167-5273 2014/10 [Refereed][Not invited]
    Background/objectives: Detecting the presence of coronary artery disease (CAD) is critically important in managing patients with heart failure of uncertain cause. The recently introduced I-123-BMIPP/(TlCl)-Tl-201 dual myocardial single-photon emission computed tomography (dual SPECT) is potentially a non-invasive diagnostic tool in detecting ischemic heart disease. The aim of our study is to evaluate the efficacy of detecting CAD by dual SPECT in patients with heart failure. Methods: We studied 501 consecutive patients (366 males, mean age 68 +/- 12 years) who were admitted because of heart failure between January 2005 and April 2009. In all patients, the dual SPECT was performed in clinically stabilized states, followed by coronary angiography within 1 week. The polar map of the SPECT image was divided into 17 segments, each scored on a scale of 0-4 based on segmental percent uptake. The mismatch score was defined as the difference between I-123-BMIPP defect score and (TlCI)-Tl-201 defect score. The uptake of (TlCl)-Tl-201 and I-123-BMIPP was analyzed quantitatively using the Heart Score View software. Results: The (TlCl)-Tl-201 defect score and mismatch score were significantly higher in CAD patients than in non-CAD patients. The receiver operating characteristic (ROC) curve revealed that the mismatch score was a significantly more effective marker in detecting the presence of CAD than (TlCl)-Tl-201 defect score (area under the curve: 0.84 versus 0.73, p < 0.05). Using the mismatch score, the sensitivity and specificity of dual SPECT in detecting CAD were 84% and 83%, respectively. Conclusion: Dual SPECT is a useful non-invasive procedure for the detection of CAD in patients with heart failure. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
  • Robin J. Ruthenborg, Jae-Jun Ban, Anum Wazir, Norihiko Takeda, Jung-whan Kim
    MOLECULES AND CELLS 37 (9) 637 - 643 1016-8478 2014/09 [Refereed][Not invited]
    Wound healing is a complex multi-step process that requires spatial and temporal orchestration of cellular and non-cellular components. Hypoxia is one of the prominent microenvironmental factors in tissue injury and wound healing. Hypoxic responses, mainly mediated by a master transcription factor of oxygen homeostasis, hypoxia-inducible factor-1 (HIF-1), have been shown to be critically involved in virtually all processes of wound healing and remodeling. Yet, mechanisms underlying hypoxic regulation of wound healing are still poorly understood. Better understanding of how the wound healing process is regulated by the hypoxic microenvironment and HIF-1 signaling pathway will provide insight into the development of a novel therapeutic strategy for impaired wound healing conditions such as diabetic wound and fibrosis. In this review, we will discuss recent studies illuminating the roles of HIF-1 in physiologic and pathologic wound repair and further, the therapeutic potentials of HIF-1 stabilization or inhibition.
  • Kenichiro Yamagata, Yuki Goto, Hiroshi Nishimasu, Jumpei Morimoto, Ryuichiro Ishitani, Naoshi Dohmae, Norihiko Takeda, Ryozo Nagai, Issei Komuro, Hiroaki Suga, Osamu Nureki
    STRUCTURE 22 (2) 345 - 352 0969-2126 2014/02 [Refereed][Not invited]
    SIRT2 deacetylates specific acetyllysine residues in diverse proteins and is implicated in a variety of cellular processes. SIRT2 inhibition thus has potentials to treat human diseases such as cancers and neurodegenerative disorders. We have recently developed a series of epsilon-trifluoroacetyllysine-containing macrocyclic peptides, which inhibit the SIRT2 activity more potently than most other known inhibitors. Here, we report the crystal structure of human SIRT2 in complex with a macrocyclic peptide inhibitor, S2iL5, at 2.5 angstrom resolution. The structure revealed that S2iL5 binds to the active site of SIRT2 through extensive interactions. A structural comparison of the SIRT2-S2iL5 complex with SIRT2 in the free form, and in complex with ADP-ribose, revealed that S2iL5 induces an open-to-closed domain movement and an unexpected helix-to-coil transition in a SIRT2-specific region. Our findings unveil the potential of macrocyclic peptides to bind target proteins by inducing dynamic structural changes.
  • Kenji Takemoto, Etsuro Hatano, Keiko Iwaisako, Masatoshi Takeiri, Naruto Noma, Saori Ohmae, Kan Toriguchi, Kazutaka Tanabe, Hirokazu Tanaka, Satoru Seo, Kojiro Taura, Keigo Machida, Norihiko Takeda, Shigehira Saji, Shinji Uemoto, Masataka Asagiri
    FEBS OPEN BIO 4 777 - 787 2211-5463 2014 [Refereed][Not invited]
    Excessive acetaminophen (APAP) use is one of the most common causes of acute liver failure. Various types of cell death in the damaged liver are linked to APAP-induced hepatotoxicity, and, of these, necrotic cell death of hepatocytes has been shown to be involved in disease pathogenesis. Until recently, necrosis was commonly considered to be a random and unregulated form of cell death; however, recent studies have identified a previously unknown form of programmed necrosis called receptor-interacting protein kinase (RIPK)-dependent necrosis (or necroptosis), which is controlled by the kinases RIPK1 and RIPK3. Although RIPK-dependent necrosis has been implicated in a variety of disease states, including atherosclerosis, myocardial organ damage, stroke, ischemia-reperfusion injury, pancreatitis, and inflammatory bowel disease. However its involvement in APAP-induced hepatocyte necrosis remains elusive. Here, we showed that RIPK1 phosphorylation, which is a hallmark of RIPK-dependent necrosis, was induced by APAP, and the expression pattern of RIPK1 and RIPK3 in the liver overlapped with that of CYP2E1, whose activity around the central vein area has been demonstrated to be critical for the development of APAP-induced hepatic injury. Moreover, a RIPK1 inhibitor ameliorated APAP-induced hepatotoxicity in an animal model, which was underscored by significant suppression of the release of hepatic enzymes and cytokine expression levels. RIPK1 inhibition decreased reactive oxygen species levels produced in APAP-injured hepatocytes, whereas CYP2E1 expression and the depletion rate of total glutathione were unaffected. Of note, RIPK1 inhibition also conferred resistance to oxidative stress in hepatocytes. These data collectively demonstrated a RIPK-dependent necrotic mechanism operates in the APAP-injured liver and inhibition of this pathway may be beneficial for APAP-induced fulminant hepatic failure. (C) 2014 The Authors. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.
  • Andrew S. Cowburn, Norihiko Takeda, Adam T. Boutin, Jung-Whan Kim, Jane C. Sterling, Manando Nakasaki, Mark Southwood, Ananda W. Goldrath, Colin Jamora, Victor Nizet, Edwin R. Chilvers, Randall S. Johnson
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 110 (43) 17570 - 17575 0027-8424 2013/10 [Refereed][Not invited]
    Vascular flow through tissues is regulated via a number of homeostatic mechanisms. Localized control of tissue blood flow, or autoregulation, is a key factor in regulating tissue perfusion and oxygenation. We show here that the net balance between two hypoxia-inducible factor (HIF) transcription factor isoforms, HIF-1 alpha and HIF-2 alpha, is an essential mechanism regulating both local and systemic blood flow in the skin of mice. We also show that balance of HIF isoforms in keratinocyte-specific mutant mice affects thermal adaptation, exercise capacity, and systemic arterial pressure. The two primary HIF isoforms achieve these effects in opposing ways that are associated with HIF isoform regulation of nitric oxide production. We also show that a correlation exists between altered levels of HIF isoforms in the skin and the degree of idiopathic hypertension in human subjects. Thus, the balance between HIF-1 alpha and HIF-2 alpha expression in keratinocytes is a control element of both tissue perfusion and systemic arterial pressure, with potential implications in human hypertension.
  • Maoqing Tong, Eiichi Watanabe, Naoki Yamamoto, Misao Nagahata-Ishiguro, Koji Maemura, Norihiko Takeda, Ryozo Nagai, Yukio Ozaki
    Biological rhythm research 44 (4) 519 - 530 0929-1016 2013/08 [Refereed][Not invited]
    Significant circadian variations exist in the frequency of cardiac arrhythmia, but few studies have examined the relation between cardiac ion channels genes and biological clocks. We investigated this relation using suprachiasmatic nuclei lesion (SCNX) and pharmacological autonomic nervous system block (ANSB) mice. Significant 24-h variations were observed in the expression of clock genes Per2, Bmal1, and Dbp and ion channel genes KCNA5, KCND2, KCHIP2, and KCNK3 in the control mice hearts. In the SCNX mice, all genes examined lost circadian rhythm. In the ANSB mice, the expressions of the three clock genes were dampened significantly but still had circadian rhythm, whereas the four ion channel gene expressions lost rhythm. Heart rate also lost circadian rhythm in both the SCNX and ANSB mice. These results suggest that some ion channel gene expressions might be regulated by the central clock in the SCN through the ANS but not the peripheral clock in the heart.
  • Tetsuya Saito, Norihiko Takeda, Eisuke Amiya, Tomoko Nakao, Hajime Abe, Hiroaki Semba, Katsura Soma, Katsuhiro Koyama, Yumiko Hosoya, Yasushi Imai, Takayuki Isagawa, Masafumi Watanabe, Ichiro Manabe, Issei Komuro, Ryozo Nagai, Koji Maemura
    FEBS LETTERS 587 (14) 2179 - 2185 0014-5793 2013/07 [Refereed][Not invited]
    Vascular endothelial growth factor-A (VEGF-A) is one of the major angiogenic factors, and its actions are primarily mediated through its two membrane receptors, VEGFR-1 and VEGFR-2. A soluble form of VEGFR-1 (sVEGFR-1) sequesters the free form of VEGF-A, and acts as a potent anti-angiogenic factor. While sVEGFR-1 is synthesized as a splice variant of VEGF-R1 gene, the interactions between VEGF-A and sVEGFR-1 remain largely unknown. Here, we show that VEGF-A upregulates sVEGF-R1 expression in human vascular endothelial cells but leaves full-length VEGF-R1 expression unchanged, and that this induction was dependent on the VEGFR-2-protein kinase C-MEK signaling pathway. The VEGF-A-induced sVEGFR-1 upregulation can operate as a negative feedback system, which if modulated can become a novel therapeutic target for regulating pathological angiogenesis. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.
  • Eisuke Amiya, Masafumi Watanabe, Norihiko Takeda, Tetsuya Saito, Taro Shiga, Yumiko Hosoya, Tomoko Nakao, Yasushi Imai, Ichiro Manabe, Ryozo Nagai, Issei Komuro, Koji Maemura
    JOURNAL OF BIOLOGICAL CHEMISTRY 288 (20) 14497 - 14509 0021-9258 2013/05 [Refereed][Not invited]
    Vascular endothelial function is impaired in hypercholesterolemia partly because of injury by modified LDL. In addition to modified LDL, free cholesterol (FC) is thought to play an important role in the development of endothelial dysfunction, although the precise mechanisms remain to be elucidated. The aim of this study was to clarify the mechanisms of endothelial dysfunction induced by an FC-rich environment. Loading cultured human aortic endothelial cells with FC induced the formation of vesicular structures composed of FC-rich membranes. Raft proteins such as phospho-caveolin-1 (Tyr-14) and small GTPase Rac were accumulated toward FC-rich membranes around vesicular structures. In the presence of these vesicles, angiotensin II-induced production of reactive oxygen species (ROS) was considerably enhanced. This ROS shifted endothelial NOS(eNOS) toward vesicle membranes and vesicles with a FC-rich domain trafficked toward perinuclear late endosomes/lysosomes, which resulted in the deterioration of eNOS Ser-1177 phosphorylation and NO production. Angiotensin II-induced ROS decreased the bioavailability of eNOS under the FC-enriched condition.
  • Tomoko Nakao, Hiroyuki Watanabe, Norihiko Takeda, Shuichiro Takanashi, Ryozo Nagai
    EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING 13 (11) 966 - 966 2047-2404 2012/11 [Refereed][Not invited]
  • Hajime Abe, Morimasa Takayama, Norihiko Takeda, Syuichiro Takanashi, Ryozo Nagai
    EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING 13 (10) 826 - 826 2047-2404 2012/10 [Refereed][Not invited]
  • Naoko Kato, Koichiro Kinugawa, Taro Shiga, Masaru Hatano, Norihiko Takeda, Yasushi Imai, Masafumi Watanabe, Atsushi Yao, Yasunobu Hirata, Keiko Kazuma, Ryozo Nagai
    JOURNAL OF CARDIOLOGY 60 (1-2) 23 - 30 0914-5087 2012/07 [Refereed][Not invited]
    Background: Little is known about depressive symptoms in heart failure with preserved ejection fraction (HFpEF, EF >= 50%). We aimed to assess the prevalence of depression, to clarify the impact of depressive symptoms upon clinical outcomes. and to identify factors associated with these symptoms in HF with reduced EF (HFrEF, EF <50%) and HFpEF. Methods and results: A total of 106 HF outpatients were enrolled. Of them, 61 (58%) had HFpEF. Most patients were male (HFrEF 80%, HFpEF 70%) and the mean of plasma B-type natriuretic peptide (BNP) level in the HFrEF group was similar to that in the HFpEF group (164.8 +/- 232.8 vs. 98.7 +/- 94.8 pg/mL). HFrEF patients were treated more frequently with beta-blockers compared with HFpEF patients (71% vs. 43%, p = 0.004). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). The prevalence of depression (CES-D score >= 16), and CES-D score did not significantly differ between HFrEF and HFpEF (24% vs. 25%, 14.1 +/- 8.3 vs. 12.1 +/- 8.3, respectively). During the 2-year follow-up, depressed patients had more cardiac death or HF hospitalization in HFrEF (55% vs. 12%, p = 0.002) and HFpEF (35% vs. 11%, p = 0.031). Cox proportional hazard analysis revealed that a higher CES-D score, indicating increased depressive symptoms, predicted cardiac events independent of BNP in HFrEF [hazard ratio (HR) 1.07, 95% confidence interval (CI) 1.01-1.131 and HFpEF (HR 1.09, 95%CI 1.04-1.15). Multiple regression analyses adjusted for BNP showed that independent predictors of depressive symptoms were non-usage of beta-blockers and being widowed or divorced in HFrEF. On the other hand, usage of warfarin was the only independent risk factor for depressive symptoms in HFpEF (all, p < 0.05). Conclusions: Depressive symptoms are common and independently predict adverse events in HFrEF/HFpEF patients. This study suggests that beta-blockers reduce depressive symptoms in HFrEF. In contrast, treatment for depression remains to be elucidated in HFpEF. (c) 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
  • Jung-whan Kim, Colin Evans, Alexander Weidemann, Norihiko Takeda, Yun Sok Lee, Christian Stockmann, Cristina Branco-Price, Filip Brandberg, Gustavo Leone, Michael C. Ostrowski, Randall S. Johnson
    CANCER RESEARCH 72 (13) 3187 - 3195 0008-5472 2012/07 [Refereed][Not invited]
    Solid tumors consist of malignant cells and associated stromal components, including fibroblastic cells that contribute to tumor growth and progression. Although tumor fibrosis and aberrant vascularization contribute to the hypoxia often found in advanced tumors, the contribution of hypoxic signaling within tumor-associated fibroblasts to tumorigenesis remains unknown. In this study, we used a fibroblast-specific promoter to create mice in which key hypoxia regulatory genes, including VHL, HIF-1 alpha, HIF-2 alpha, and VEGF-A, were knocked out specifically in tumor stromal fibroblasts. We found that loss of HIF-1 alpha and its target gene VEGF-A accelerated tumor growth in murine model of mammary cancer. HIF-1 alpha and VEGF-A loss also led to a reduction in vascular density and myeloid cell infiltration, which correlated with improved tumor perfusion. Together, our findings indicate that the fibroblast HIF-1 alpha response is a critical component of tumor vascularization. Cancer Res; 72(13); 3187-95. (C) 2012 AACR.
  • Hiroaki Semba, Hitoshi Sawada, Tokuhisa Uejima, Norihiko Takeda, Katsura Soma, Hajime Abe, Takeshi Yamashita, Ryozo Nagai
    INTERNATIONAL HEART JOURNAL 53 (4) 230 - 233 1349-2365 2012/07 [Refereed][Not invited]
    Left ventricular outflow tract obstruction (LVOTO) is commonly observed in patients with hypertrophic cardiomyopathy (HCM) or left ventricular hypertrophy (LVH). While some patients develop LVOTO at rest, it can also be provoked by physical exertion, and hence termed latent LVOTO (L-LVOTO). Recent reports demonstrated that L-LVOTO develops not only in LVH patients, but also in patients without LVH (non-LVH). However, the prevalence and clinical prognosis of non-LVH patients with L-LVOTO are not yet elucidated. In this study, we retrospectively investigated the echocardiographic features of patients with malignancy who underwent dobutamine stress echocardiography (DSE) to evaluate preoperative cardiac risk. One hundred ninety-nine patients were found not to have LVH or coronary artery disease. Among them, 106 patients exhibited L-LVOTO after DSE. We next compared the baseline echocardiographic features of L-LVOTO (+) patients with those of L-LVOTO (-) patients, and identified the left ventricular outflow tract (LVOT) ratio (systolic LVOT diameter/diastolic LVOT diameter) as a significant predictor of L-LVOTO. An LVOT ratio <= 0.83 was the best cutoff value to detect the presence of L-LVOTO, with a sensitivity of 81.1% and specificity of 80.6%. Overall, L-LVOTO was found to develop in almost half of non-LVH patients with malignancy, in addition, the baseline LVOT ratio was strongly related to the presence of L-LVOTO in non-LVH patients. Therefore, patients with dynamic LVOT narrowing may benefit from DSE to detect the presence of L-LVOTO. (Int Heart J 2012; 53: 230-233)
  • Hiroaki Semba, Koichiro Kinugawa, Norihiko Takeda, Taro Shiga, Go Nishimura, Tsukasa Inajima, Yuichi Uchino, Hiroshi Iwata, Eriko Hasumi, Hajime Abe, Yumiko Terada, Akihiko Yonenaga, Yasunobu Hirata, Ryozo Nagai
    INTERNATIONAL HEART JOURNAL 53 (1) 72 - 74 1349-2365 2012/01 [Refereed][Not invited]
    While diuretic drugs are commonly used in patients with congestive heart failure, the efficacy of their long-term use still remains controversial. Recently, a new class of diuretics, vasopressin receptor 2 antagonists, has been launched, and tolvaptan is one such drug. We describe our initial experience with this novel agent. Tolvaptan is potentially useful for treatment of heart failure patients with fluid overload who are refractory to conventional diuretic therapies. (Int Heart J 2012; 53: 72-74)
  • Katsura Soma, Hajime Abe, Norihiko Takeda, Yukako Shintani, Yutaka Takazawa, Toshiya Kojima, Katsuhito Fujiu, Hiroaki Semba, Hiroshi Yamashita, Yasunobu Hirata, Masashi Fukayama, Ryozo Nagai
    INTERNATIONAL HEART JOURNAL 53 (1) 75 - 77 1349-2365 2012/01 [Refereed][Not invited]
    Mitral and aortic valve regurgitation is commonly found in osteogenesis imperfecta (OI) patients, however, little is known about the myocardial involvement in this disorder. An 82-year-old man with OI developed heart failure and was admitted to our hospital. Echocardiogram revealed severe mitral regurgitation without left ventricular (LV) dilatation, but with LV wall thickening. Histological analysis exhibited interstitial fibrosis of the myocardium in addition to myxoid changes of the mitral leaflet. These findings suggest that OI patients may develop LV remodeling together with diastolic dysfunction. (Int Heart J 2012; 53: 75-77)
  • Hajime Abe, Norihiko Takeda, Hajime Aoki, Ryozo Nagai
    INTERNAL MEDICINE 51 (10) 1275 - 1275 0918-2918 2012 [Refereed][Not invited]
  • Tetsuya Saito, Masafumi Watanabe, Toshiya Kojima, Takayoshi Matsumura, Hideo Fujita, Arihiro Kiyosue, Masao Takahashi, Norihiko Takeda, Koji Maemura, Hiroshi Yamashita, Yasunobu Hirata, Shuhei Komatsu, Kuni Ohtomo, Ryozo Nagai
    INTERNATIONAL HEART JOURNAL 52 (5) 327 - 330 1349-2365 2011/09 [Refereed][Not invited]
    Interrupted inferior vena cava (IVC) with azygos continuation is a rare congenital anomaly, and is frequently associated with other cardiovascular malformations and situs anomalies, such as left isomerism. These patients usually develop deep vein thrombosis (DVT), and asymptomatic patients above 60 years of age are very rare. Here we report a case of interrupted IVC which we diagnosed in a 72-year-old woman. She was admitted to our hospital suffering from heart failure and supraventricular tachycardia. Echocardiography detected secundum atrial septal defect (ASD). An abnormal paravertebral pleural line on the chest X-rays indicated the existence of venous anomaly. Anatomical images obtained by Multidetector Computed Tomography (MDCT) helped us to successfully perform right heart catheterization procedures through azygos continuation including blood sampling from pulmonary veins. Even in elderly patients, a careful examination of chest X-rays can indicate undiagnosed venous anomalies; thus, it is critically important before planning surgical or interventional procedures. (Int Heart J 2011; 52: 327-330)
  • Norihiko Takeda, Koji Maemura
    JOURNAL OF CARDIOLOGY 57 (3) 249 - 256 0914-5087 2011/05 [Refereed][Not invited]
    Both the physiological and pathological functions of cardiovascular organs are closely related to circadian rhythm, an endogenously driven 24-h cycle. Heart rate, blood pressure, and endothelial function show diurnal variations within a day. The onset of cardiovascular disorders such as acute coronary syndrome, atrial arrhythmia, and subarachinoid hemorrhage also exhibits diurnal oscillation. Recent progress in studying the functions and molecular mechanisms of the biological clock brought forth the idea that intrinsic circadian rhythms are tightly related to cardiovascular pathology. The center of the biological clock exists in the suprachiasmatic nucleus in the hypothalamus. In addition to this central clock, each organ has its own biological clock system, termed the peripheral clock. Each cardiovascular tissue or cell, including heart and aortic tissue, cardiomyocyte, vascular smooth muscle cell, and vascular endothelial cell also has intrinsic biological rhythm. Until recently, little was known about the roles of peripheral clocks in cardiovascular organs. However, studies using genetically engineered mice revealed their contributions during the process of disease progression. Loss of synchronization between the internal clock and external stimuli can induce cardiovascular organ damage. Discrepancy in the phases between the central and peripheral clocks also seems to contribute to progression of the disorders. Elucidation of the precise roles of biological clocks in cardiovascular organs will provide us with more profound insights into the relevance of the circadian rhythm in cardiac pathology. Moreover, identification of the modalities with which we can manipulate the phase of each peripheral clock will enable us to establish a novel chronotherapeutic approach. This time-of-day based strategy may innovate a new paradigm in the prevention and treatment of cardiovascular disorders. (C) 2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
  • Satomi Seki, Naoko Kato, Naomi Ito, Koichiro Kinugawa, Minoru Ono, Noboru Motomura, Atsushi Yao, Masafumi Watanabe, Yasushi Imai, Norihiko Takeda, Masashi Inoue, Masaru Hatano, Keiko Kazuma
    EUROPEAN JOURNAL OF CARDIOVASCULAR NURSING 10 (1) 22 - 30 1474-5151 2011/03 [Refereed][Not invited]
    Background and aims: Assessing the health related quality of life (HRQOL) in patients with a disease specific scale is essential. The purpose of this study was to develop the Japanese version of the coronary revascularisation outcome questionnaire (CROQ), a disease-specific scale to measure HRQOL before and after coronary revascularisation. Methods: The English version of the questionnaire was translated into Japanese; some terms were revised, and some items were eliminated to suit the Japanese medical environment. Eight patients filled out the questionnaire, which was then analyzed for face validity. In the field study, subjects were recruited from a university hospital in Tokyo, and questionnaires were given to fill out. In terms of statistical analysis, factor analysis, internal consistency, known-groups validity, concurrent validity with using Short-Form36 (SF-36) and Seattle Angina Questionnaire-Japanese version (SAQ-J), and test-retest reliability were assessed. Results: Informed consents were obtained from 356 patients, and out of 325 patients responded in the field study (91.3%). The factor structure of CROQ-Japanese version (CROQ-J) was similar to that of the original version. Cronbach's alpha ranged from 0.78 to 0.92. The concurrent validity was mostly supported by the pattern of association between CROQ-J, SAQ-J, and SF-36. Patients without chest symptoms had significantly higher scores of CROQ-J than those with chest symptoms. On the basis of analysis of the test-retest reliability, intra-class correlation coefficients were close to 0.70. Conclusions: The Japanese translation of CROQ is a valid and reliable scale for assessing the patient's HRQOL in CAD. (C) 2010 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
  • Christian Stockmann, Santina Kirmse, Iris Helfrich, Alexander Weidemann, Norihiko Takeda, Andrew Doedens, Randall S. Johnson
    JOURNAL OF INVESTIGATIVE DERMATOLOGY 131 (3) 797 - 801 0022-202X 2011/03 [Refereed][Not invited]
  • Alexander Weidemann, Tim U. Krohne, Edith Aguilar, Toshihide Kurihara, Norihiko Takeda, Michael I. Dorrell, M. Celeste Simon, Volker H. Haase, Martin Friedlander, Randall S. Johnson
    GLIA 58 (10) 1177 - 1185 0894-1491 2010/08 [Refereed][Not invited]
    Vascular/parenchymal crosstalk is increasingly recognized as important in the development and maintenance of healthy vascularized tissues. The retina is an excellent model in which to study the role of cell type-specific contributions to the process of blood vessel and neuronal growth. During retinal vascular development, glial cells such as astrocytes provide the template over which endothelial cells migrate to form the retinal vascular network, and hypoxia-regulated vascular endothelial growth factor (VEGF) has been demonstrated to play a critical role in this process as well as pathological neovascularization. To investigate the nature of cell-specific contributions to this process, we deleted VEGF and its upstream regulators, the hypoxia-inducible transcription factors HIF-1 alpha and HIF-2 alpha, and the negative regulator of HIF alpha, von Hippel Lindau protein (VHL), in astrocytes. We found that loss of hypoxic response and VEGF production in astrocytes does not impair normal development of retinal vasculature, indicating that astrocyte-derived VEGF is not essential for this process. In contrast, using a model of oxygen-induced ischemic retinopathy, we show that astrocyte-derived VEGF is essential for hypoxia-induced neovascularization. Thus, we demonstrate that astrocytes in the retina have highly divergent roles during developmental, physiological angiogenesis, and ischemia-driven, pathological neovascularization. (C) 2010 Wiley-Liss, Inc.
  • Norihiko Takeda, Koji Maemura
    HYPERTENSION RESEARCH 33 (7) 645 - 651 0916-9636 2010/07 [Refereed][Not invited]
    Cardiovascular functions, including blood pressure and vascular functions, show diurnal oscillation. Circadian variations have been clearly shown in the occurrence of cardiovascular events such as acute myocardial infarction. Circadian rhythm strongly influences human biology and pathology. The identification and characterization of mammalian clock genes revealed that they are expressed almost everywhere throughout the body in a circadian manner. In contrast to the central clock in the suprachiasmatic nucleus (SCN), the clock in each tissue or cell is designated as a peripheral clock. It is now accepted that peripheral clocks have their own roles specific to each peripheral organ by regulating the expression of clock-controlled genes (CCGs), although the oscillation mechanisms of the peripheral clock are similar to that of the SCN. However, little was known about how the peripheral clock in the vasculature contributes to the process of cardiovascular disorders. The biological clock allows each organ or cell to anticipate and prepare for changes in external stimuli. Recent evidence obtained using genetically engineered mice with disrupted circadian rhythm showed a novel function of the internal clock in the pathogenesis of endothelial dysfunction, hypertension and hemostasis. Loss of synchronization between the central and peripheral clock also contributes to the pathogenesis of cardiovascular diseases, as restoration of clock homeostasis could prevent disease progression. Identification of CCGs in each organ, as well as discovery of tools to manipulate the phase of each biological clock, will be of great help in establishing a novel chronotherapeutic approach to the prevention and treatment of cardiovascular disorders. Hypertension Research (2010) 33, 645-651; doi: 10.1038/hr.2010.68; published online 7 May 2010
  • Norihiko Takeda, Koji Maemura
    ADVANCED DRUG DELIVERY REVIEWS 62 (9-10) 956 - 966 0169-409X 2010/07 [Refereed][Not invited]
    Cardiovascular functions such as heart rate and blood pressure show 24 h variation. The incidence of cardiovascular diseases including acute myocardial infarction and arrhythmia also exhibits diurnal variation. The center of this circadian clock is located in the suprachiasmatic nucleus in the hypothalamus. However, recent findings revealed that each organ, including cardiovascular tissues, has its own internal clock, which has been termed a peripheral clock. The functional roles played by peripheral clocks have been reported recently. Since the peripheral clock is considered to play considerable roles in the processes of cardiac tissues, the identification of genes specifically regulated by this clock will provide insights into its role in the pathogenesis of cardiovascular disorders. In addition, the discovery of small compounds that modulate the peripheral clock will help to establish chronotherapeutic approaches. Understanding the biological relevance of the peripheral clock will provide novel approaches to the prevention and treatment of cardiovascular diseases. (C) 2010 Elsevier B.V. All rights reserved.
  • Satomi Seki, Naoko Kato, Naomi Ito, Koichiro Kinugawa, Minoru Ono, Noboru Motomura, Atsushi Yao, Masafumi Watanabe, Yasushi Imai, Norihiko Takeda, Masashi Inoue, Masaru Hatano, Keiko Kazuma
    Asian Nursing Research 4 (2) 57 - 63 1976-1317 2010/07 [Refereed][Not invited]
    Purpose The aim of this study was to evaluate the validity and reliability of the Seattle Angina Questionnaire, Japanese version (SAQ-J) as a disease-specific health outcome scale in patients with coronary artery disease. Methods Patients with coronary artery disease were recruited from a university hospital in Tokyo. The patients completed self-administered questionnaires, and medical information was obtained from the subjects medical records. Face validity, concurrent validity evaluated using Short Form 36 (SF-36), known group differences, internal consistency, and test-retest reliability were statistically analyzed. Results A total of 354 patients gave informed consent, and 331 of them responded (93.5%). The concurrent validity was mostly supported by the pattern of association between SAQ-J and SF-36. The patients without chest symptoms showed significantly higher SAQ-J scores than did the patients with chest symptoms in 4 domains. Cronbachs alpha ranged from .51 to .96, meaning that internal consistency was confirmed to a certain extent. The intraclass correlation coefficient of most domains was higher than the recommended value of 0.70. The weighted kappa ranged from .24 to .57, and it was greater than .4 for 14 of the 19 items. Conclusions The SAQ-J could be a valid and reliable disease-specific scale in some part for measuring health outcomes in patients with coronary artery disease, and requires cautious use.
  • Christian Stockmann, Yann Kerdiles, Marc Nomaksteinsky, Alexander Weidemann, Norihiko Takeda, Andrew Doedens, Antonio X. Torres-Collado, Luisa Iruela-Arispe, Victor Nizet, Randall S. Johnson
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 107 (9) 4329 - 4334 0027-8424 2010/03 [Refereed][Not invited]
    Tissue injury initiates a complex series of events that act to restore structure and physiological homeostasis. Infiltration of inflammatory cells and vascular remodeling are both keystones of this process. However, the role of inflammation and angiogenesis in general and, more specifically, the significance of inflammatory cell-derived VEGF in this context are unclear. To determine the role of inflammatory cell-derived VEGF in a clinically relevant and chronically inflamed injury, pulmonary fibrosis, we deleted the VEGF-A gene in myeloid cells. In a model of pulmonary fibrosis in mice, deletion of VEGF in myeloid cells resulted in significantly reduced formation of blood vessels; however, it causes aggravated fibrotic tissue damage. This was accompanied by a pronounced decrease in epithelial cell survival and a striking increase in myofibroblast invasion. The drastic increase in fibrosis following loss of myeloid VEGF in the damaged lungs was also marked by increased levels of hypoxia-inducible factor (HIF) expression and Wnt/beta-catenin signaling. This demonstrates that the process of angiogenesis, driven by myeloid cell-derived VEGF, is essential for the prevention of fibrotic damage.
  • Norihiko Takeda, Ellen L. O'Dea, Andrew Doedens, Jung-Whan Kim, Alexander Weidemann, Christian Stockmann, Masataka Asagiri, M. Celeste Simon, Alexander Hoffmann, Randall S. Johnson
    GENES & DEVELOPMENT 24 (5) 491 - 501 0890-9369 2010/03 [Refereed][Not invited]
    Hypoxic response and inflammation both involve the action of the hypoxia-inducible transcription factors HIF-1 alpha and HIF-2 alpha. Previous studies have revealed that both HIF-alpha proteins are in a number of aspects similarly regulated post-translationally. However, the functional interrelationship of these two isoforms remains largely unclear. The polarization of macrophages controls functionally divergent processes; one of these is nitric oxide (NO) production, which in turn is controlled in part by HIF factors. We show here that the HIF-alpha isoforms can be differentially activated: HIF-1 alpha is induced by Th1 cytokines in M1 macrophage polarization, whereas HIF-2 alpha is induced by Th2 cytokines during an M2 response. This differential response was most evident in polarized macrophages through HIF-alpha isoform-specific regulation of the inducible NO synthase gene by HIF-1 alpha, and the arginase1 gene by HIF-2 alpha. In silico modeling predicted that regulation of overall NO availability is due to differential regulation of HIF-1 alpha versus HIF-2 alpha, acting to, respectively, either increase or suppress NO synthesis. An in vivo model of endotoxin challenge confirmed this; thus, these studies reveal that the two homologous transcription factors, HIF-1 alpha and HIF-2 alpha, can have physiologically antagonistic functions, but that their antiphase regulation allows them to coordinately regulate NO production in a cytokine-induced and transcription-dependent fashion.
  • Alexander Weidemann, Yann M. Kerdiles, Karl X. Knaup, Christopher A. Rafie, Adam T. Boutin, Christian Stockmann, Norihiko Takeda, Miriam Scadeng, Andy Y. Shih, Volker H. Haase, M. Celeste Simon, David Kleinfeld, Randall S. Johnson
    JOURNAL OF CLINICAL INVESTIGATION 119 (11) 3373 - 3383 0021-9738 2009/11 [Refereed][Not invited]
    A key adaptation to environmental hypoxia. is an increase in erythropoiesis, driven by the hormone erythropoietin (EPO) through what is traditionally thought to be primarily a renal response. However, both neurons and astrocytes (the largest subpopulation of glial cells in the CNS) also express EPO following ischemic injury, and this response is known to ameliorate damage to the brain. To investigate the role of glial cells as a component of the systemic response to hypoxia, we created astrocyte-specific deletions of the murine genes encoding the hypoxia-inducible transcription factors HIF-1 alpha and HIF-2 alpha and their negative regulator von Hippel-Lindau (VHL) as well as astrocyte-specific deletion of the HIF target gene Vegf. We found that loss of the hypoxic response in astrocytes does not cause anemia in mice but is necessary for approximately 50% of the acute erythropoietic response to hypoxic stress. In accord with this, erythroid progenitor cells and reticulocytes were substantially reduced in number in mice lacking HIF function in astrocytes following hypoxic stress. Thus, we have demonstrated that the glial component of the CNS is an essential component of hypoxia-induced erythropoiesis.
  • Naoko Kato, Koichiro Kinugawa, Naomi Ito, Atsushi Yao, Masafumi Watanabe, Yasushi Imai, Norihiko Takeda, Masaru Hatano, Keiko Kazuma
    HEART & LUNG 38 (5) 398 - 409 0147-9563 2009/09 [Refereed][Not invited]
    BACKGROUND: Adherence to self-care behavior is important for patients with heart failure (HF) to prevent exacerbation of HF. The aim of this study was to evaluate adherence, identify associated factors, and clarify the impact of previous HF hospitalizations on adherence in outpatients with HF. METHODS: A total of 116 outpatients completed a questionnaire, including the Japanese version of the European Heart Failure Self-Care Behavior Scale, to assess adherence. RESULTS: Regardless of previous hospitalizations, adherence to seek help if HF worsened was poor. Multivariate analysis adjusted for age and brain natriuretic peptide showed that diabetes mellitus and being employed were independent predictors of poorer adherence to self-care behavior (P = .03, P = .02, respectively), but the experience of previous HF hospitalizations was not a predictor. CONCLUSIONS: Self-care strategies for HF should target patients with diabetes mellitus and employed patients. Further study is necessary to develop effective programs for such patients. (Heart Lung (R) 2009; 38:398-409.)
  • Christian Stockmann, Andrew Doedens, Alexander Weidemann, Na Zhang, Norihiko Takeda, Joshua I. Greenberg, David A. Cheresh, Randall S. Johnson
    NATURE 456 (7223) 814 - U107 0028-0836 2008/12 [Refereed][Not invited]
    Angiogenesis and the development of a vascular network are required for tumour progression, and they involve the release of angiogenic factors, including vascular endothelial growth factor ( VEGF-A), from both malignant and stromal cell types(1). Infiltration by cells of the myeloid lineage is a hallmark of many tumours, and in many cases the macrophages in these infiltrates express VEGF-A(2). Here we show that the deletion of inflammatory-cell-derived VEGF- A attenuates the formation of a typical high-density vessel network, thus blocking the angiogenic switch in solid tumours in mice. Vasculature in tumours lacking myeloid- cell-derived VEGF-A was less tortuous, with increased pericyte coverage and decreased vessel length, indicating vascular normalization. In addition, loss of myeloid-derived VEGF- A decreases the phosphorylation of VEGF receptor 2 (VEGFR2) in tumours, even though overall VEGF- A levels in the tumours are unaffected. However, deletion of myeloid- cell VEGF- A resulted in an accelerated tumour progression in multiple subcutaneous isograft models and an autochthonous transgenic model of mammary tumorigenesis, with less overall tumour cell death and decreased tumour hypoxia. Furthermore, loss of myeloid- cell VEGF- A increased the susceptibility of tumours to chemotherapeutic cytotoxicity. This shows that myeloid- derived VEGF- A is essential for the tumorigenic alteration of vasculature and signalling to VEGFR2, and that these changes act to retard, not promote, tumour progression.
  • Elsuke Amiya, Koji Maemura, Norihiko Takeda, Tetsuya Saito, Taro Shiga, Yumiko Hosoya, Tomoko Nakao, Yasushi Imai, Ryozo Nagai
    CIRCULATION 118 (18) S366 - S366 0009-7322 2008/10 [Refereed][Not invited]
  • Norihiko Takeda, Koji Maemura, Shuichi Horie, Katsutaka Oishi, Yasushi Imai, Tomohiro Harada, Tetsuya Saito, Taro Shiga, Eisuke Amiya, Ichiro Manabe, Norio Ishida, Ryozo Nagai
    JOURNAL OF BIOLOGICAL CHEMISTRY 282 (45) 32561 - 32567 0021-9258 2007/11 [Refereed][Not invited]
    Cardiovascular diseases are closely related to circadian rhythm, which is under the control of an internal biological clock mechanism. Although a biological clock exists not only in the hypothalamus but also in each peripheral tissue, the biological relevance of the peripheral clock remains to be elucidated. In this study we searched for clock- controlled genes in vascular endothelial cells using microarray technology. The expression of a total of 229 genes was up- regulated by CLOCK/ BMAL2. Among the genes that we identified, we examined the thrombomodulin ( TM) gene further, because TM is an integral membrane glycoprotein that is expressed primarily in vascular endothelial cells and plays a major role in the regulation of intravascular coagulation. TM mRNA and protein expression showed a clear circadian oscillation in the mouse lung and heart. Reporter analyses, gel shift assays, and chromatin immunoprecipitation analyses using the TM promoter revealed that a heterodimer of CLOCK and BMAL2 binds directly to the E- box of the TM promoter, resulting in TM promoter transactivation. Indeed, the oscillation of TM gene expression was abolished in clock mutant mice, suggesting that TM expression is regulated by the clock gene in vivo. Finally, the phase of circadian oscillation of TM mRNA expression was altered by temporal feeding restriction, suggesting TM gene expression is regulated by the peripheral clock system. In conclusion, these data suggest that the peripheral clock in vascular endothelial cells regulates TM gene expression and that the oscillation of TM expression may contribute to the circadian variation of cardiovascular events.
  • Shiga Taro, Maemura Koji, Imai Yasushi, Kawanami Daiji, Takeda Norihiko, Ando Jiro, Morita Toshihiro, Manabe Ichiro, Hayashi Dobun, Sugiyama Akira, Miyamoto Kyoko, Sagara Mina, Ito Yukio, Yamazaki Tsutomu, Hirata Yasunobu, Kodama Tatsuhiko, Nagai Ryozo
    CIRCULATION 116 (16) 363  0009-7322 2007/10 [Refereed][Not invited]
  • Ichiro Kojima, Tetsuhiro Tanaka, Reiko Inagi, Hideki Kato, Toshiharu Yamashita, Ai Sakiyama, Osamu Ohneda, Norihiko Takeda, Masataka Sata, Toshio Miyata, Toshiro Fujita, Masaomi Nangaku
    JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 18 (4) 1218 - 1226 1046-6673 2007/04 [Refereed][Not invited]
    Central to cellular responses to hypoxic environment is the hypoxia-inducible factor (HIF) transcriptional control system. A role for HIF-2 alpha was investigated in a model of renal ischemia-reperfusion injury (IRI) associated with oxidative stress using HIF-2 alpha knockdown mice. In these mice, HIF-2 alpha expression was approximately one half that of wild-type mice, whereas HIF-1 alpha expression was equivalent. HIF-2 alpha knockdown mice were more susceptible to renal IRI, as indicated by elevated blood urea nitrogen levels and semiquantitative histologic analysis. Immunostaining with markers of oxidative stress showed enhanced oxidative stress in the kidney of HIF-2 alpha knockdown mice, which was associated with peritubular capillary loss. Real-time quantitative PCR analysis showed decreased expression of antioxidative stress genes in the HIF-2 alpha knockdown kidneys. Studies that used small interference RNA confirmed regulation of the antioxidative stress genes in cultured endothelial cells. Although HIF-2 alpha knockdown mice were anemic, serum erythropoietin levels were not significantly increased, reflecting inappropriate response to anemia as a result of HIF-2 alpha knockdown. Experiments that used hemodiluted mice with renal ischemia demonstrated that anemia of this degree did not affect susceptibility to ischemia. Knockdown of HIF-2 alpha in inflammatory cells by bone marrow transplantation experiments demonstrated that HIF-2 alpha in inflammatory cells did not contribute to susceptibility to renal IRL Restoration of HIF-2 alpha in endothelium by intercrossing with Tie1-Cre mice ameliorated renal injury by IRI, demonstrating a specific role of endothelial HIF-2 alpha. These results suggest that HIF-2 alpha in the endotheliunt has a protective role against ischemia of the kidney via amelioration of oxidative stress.
  • Shiga Taro, Maemura Koji, Imai Yasushi, Kawanami Daiji, Takeda Norihiko, Ando Jiro, Morita Toshihiro, Manabe Ichiro, Hayashi Dobun, Ohtsu Hiroshi, Sugiyama Akira, Miyamoto Kyoko, Sagara Mina, Ito Yukio, Yamazaki Tsutomu, Hirata Yasunobu, Kodama Tatsuhiko, Nagai Ryozo
    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 49 (9) 377A  0735-1097 2007/03 [Refereed][Not invited]
  • Koji Maemura, Norihiko Takeda, Ryozo Nagai
    JOURNAL OF PHARMACOLOGICAL SCIENCES 103 (2) 134 - 138 1347-8613 2007/02 [Refereed][Not invited]
    The cardiovascular diseases are closely related to circadian rhythm, which is under the control of the biological clock. Clock genes show circadian oscillation not only in the suprachiasmatic nucleus but also in peripheral tissues, suggesting the existence of the peripheral clock. We previously demonstrated that plasminogen activator inhibitor-1 (PAI-1) might be an output gene of the peripheral clock. To further elucidate the functional relevance of the peripheral clock in the cardiovascular system, we screened target genes of the peripheral clock by cDNA microarray analysis. A total of 29 genes including transcription factor, growth factors, and membrane receptors were upregulated by CLOCK/BMAL and showed circadian oscillation. These results suggest that cardiovascular systems have their own peripheral clocks, and at least in part, they may regulate the circadian oscillation of cardiovascular function directly. These results potentially provide a molecular basis for the circadian variation of cardiovascular function and novel strategies for the prevention and treatment of cardiovascular diseases.
  • Norihiko Takeda, Koji Maemura
    BIOLOGICAL RHYTHM RESEARCH 38 (3) 233 - 245 0929-1016 2007 [Refereed][Not invited]
    The incidence of heart attacks increases in the early morning. This circadian oscillation is closely related to the function of the internal biological clock. In this article, we review the chronobiology of acute myocardial infarction (AMI) from the viewpoint of molecular biology.
  • Kazuo Asada, Masaru Hatano, Norihiko Takeda, Yasutomi Higashikuni, Kan Saito, Nobukazu Ishizaka, Yasunobu Hirata, Ryozo Nagai
    INTERNAL MEDICINE 46 (15) 1267 - 1268 0918-2918 2007 [Refereed][Not invited]
  • Imai Yasushi, Hayashi Dobun, Manabe Ichiro, Harada Tomohiro, Takeda Norihiko, Monzen Koshiro, Kohro Takahide, Yamazaki Tadashi, Maemura Koji, Sugiyama Takao, Yamazaki Tsutomu, Nagai Ryozo
    Circulation Journal 70 (Suppl.I) 609 - 609 1346-9843 2006/03
  • D Kawanami, K Maemura, N Takeda, T Harada, T Nojiri, T Saito, Manabe, I, Y Imai, R Nagai
    ATHEROSCLEROSIS 185 (1) 39 - 46 0021-9150 2006/03 [Refereed][Not invited]
    Recent studies have shown that C-reactive protein (CRP) is not just a predictor of cardiovascular events but also acts directly as a proinflammatory stimulus in vascular cells. In this report, we studied the molecular mechanisms underlying vascular cellular adhesion molecule-1 (VCAM-1) induction by CRP. CRP-induced VCAM-1 mRNA expression and this induction was inhibited by protein kinase C (PKC) inhibitors, p38 mitogen-activated protein kinase (MAPK) inhibitor, and tyrosine kinase inhibitors. In addition, parthenolide, a nuclear factor kappa B (NF-kappa B) inhibitor, abolished VCAM-1 induction. Moreover, CRP increased VCAM-1 promoter activity, indicating that CRP induces VCAM-1 mRNA expression at the transcriptional level. Mutation of NF-kappa B-binding sites resulted in a loss of induction. Finally, an electrophoretic mobility shift assay confirmed binding of the p65 subunit of NF-kappa B to kappa B-binding sites. Taken together, our findings suggest that VCAM-1 induction by CRP is mediated by PKC, p38MAPK, tyrosine kinase and the NF-kappa B-dependent signaling pathways in vascular endothelial cells. (c) 2005 Elsevier Ireland Ltd. All rights reserved.
  • Y Imai, T Taketani, K Maemura, N Takeda, T Harada, T Nojiri, D Kawanami, K Monzen, D Hayashi, Y Murakawa, M Ohno, Y Hirata, T Yamazaki, S Takamoto, R Nagai
    CIRCULATION JOURNAL 69 (8) 994 - 995 1346-9843 2005/08 [Refereed][Not invited]
    A 60 year-old male was referred for treatment of a cardiac myxoma in the right atrium. He had a past history of left atrial cardiac myxoma at age 49 and pituitary microadenoma related to acromegaly at age 55. He did not have a family history of cardiac neoplasm or endocrinopathy. The intracardiac tumor was resected and its pathology was compatible with myxoma. A diagnosis of Carney complex (CNC) was made because the diagnostic criteria of this neoplastic syndrome were satisfied by the presence of recurrent cardiac myxoma, endocrine tumor and spotty skin pigmentation. In genetic analysis novel frame shift mutation was detected in exon 2 in a heterozygous fashion in the causative gene of CNC, protein kinase A regulatory subunit 1 alpha (PRKAR1A). This genetic mutation is thought to cause haplo-insufficiency of PRKAR1A resulting in tumorigenesis. Although it is the most common, usually benign, cardiac tumor, myxoma can cause a critical clinical situation and thus detecting the PRKAR1A mutation can assist with prognosis.
  • Imai Yasushi, Hayashi Dobun, Manabe Ichiro, Ohishi Yumiko, Harada Tomohiro, Takeda Norihiko, Nishimura Go, Nojiri Takefumi, Tsushima Kensuke, Kawanami Daiji, Yamazaki Tadashi, Monzen Koshiro, Maemura Koji, Yamazaki Tsutomu, Nagai Ryouzou
    Circulation Journal 69 (Suppl.I) 220 - 220 1346-9843 2005/03
  • H Hamaguchi, K Fujimoto, T Kawamoto, M Noshiro, K Maemura, N Takeda, R Nagai, M Furukawa, S Honma, K Honma, H Kurihara, Y Kato
    BIOCHEMICAL JOURNAL 382 (Pt 1) 43 - 50 0264-6021 2004/08 [Refereed][Not invited]
    Dec2, a member of the basic helix-loop-helix superfamily, is a recently confirmed regulatory protein for the clockwork system. Transcripts of Dec2, as well as those of its related gene Dec1, exhibit a striking circadian oscillation in the suprachiasmatic nucleus, and Dec2 inhibits transcription from the Per1 promoter induced by Clock/Bmal1 [Honma, Kawamoto, Takagi, Fujimoto, Sato, Noshiro, Kato and Honma (2002) Nature (London) 419, 841-844]. It is known that mammalian circadian rhythms are controlled by molecular clockwork systems based on negative feedback loop(s), but the molecular mechanisms for the circadian regulation of Dec2 gene expression have not been clarified. We show here that transcription of the Dec2 gene is regulated by several clock molecules and a negative-feedback loop. Luciferase and gel retardation assays showed that expression of Dec2 was negatively regulated by binding of Dec2 or Dec1 to two CACGTG E-boxes in the Dec2 promoter. Forced expression of Clock/Bmal1 and Clock/Bmal2 markedly increased Dec2 mRNA levels, and upregulated the transcription of the Dec2 gene through the CACGTG E-boxes. Like Dec, Cry and Per also suppressed Clock/Bmalinduced transcription from the Dec2 promoter. Moreover, the circadian expression of Dec2 transcripts was abolished in the kidney of Clock/Clock mutant mice. These findings suggest that the Clock/Bmal heterodimer enhances Dec2 transcription via the CACGTG E-boxes, whereas the induced transcription is suppressed by Dec2, which therefore must contribute to its own rhythmic expression. In addition, Cry and Per may also modulate Dec2 transcription.
  • N Takeda, K Maemura, Y Imai, T Harada, D Kawanami, T Nojiri, Manabe, I, R Nagai
    CIRCULATION RESEARCH 95 (2) 146 - 153 0009-7330 2004/07 [Refereed][Not invited]
    Endothelial PAS domain protein 1 (EPAS1) is a basic-helix-loop-helix/PAS domain transcription factor that is expressed preferentially in vascular endothelial cells. EPAS1 shares high homology with hypoxia-inducible factor-1alpha (HIF-1alpha) and is reported to transactivate vascular endothelial growth factor (VEGF), fetal liver kinase-1 (Flk-1), and Tie2 promoters. In this study, we analyzed the role of EPAS1 in the process of angiogenesis. Using microarray technology, we looked for target genes regulated by EPAS1 in vascular endothelial cells. A total of 130 genes were upregulated by EPAS1, including fms-like tyrosine kinase-1 (Flt-1). Reporter analysis using human Flt-1 promoter and gel mobility shift assays showed that the heterodimer of EPAS1 and aryl hydrocarbon receptor nuclear translocator binds directly to HIF-1-binding site upstream of Flt-1 promoter and transactivates it. Small interfering RNA targeted to EPAS1 but not HIF-1alpha attenuated desferrioxamine-induced Flt-1 mRNA expression, thus EPAS1 is thought to play an essential role in hypoxic induction of Flt-1 gene. Furthermore, using mouse wound healing models, we demonstrated that adenovirus-mediated delivery of EPAS1 gene significantly induced the expression of VEGF, Flt-1, Flk-1, and Tie2 mRNA at the wound site and promoted mature angiogenesis. The proportion of the number of mural cells in newly formed vessels was significantly higher in EPAS1-treated wound area than VEGF-treated area. In conclusion, EPAS1 promotes Flt-1 gene expression and induces mRNA expression of VEGF, Flk-1, and Tie2, leading to enhancement of mature angiogenesis in vivo. Thus, EPAS1 may contribute to the construction of mature vessels by modulating the coordinated expressions of VEGF, Flt-1, Flk-1, and Tie2.
  • Imai Yasushi, Harada Tomohiro, Hayashi Dobun, Nishimura Go, Tsushima Kensuke, Nojiri Takefumi, Monzen Koshiro, Yamazaki Tadashi, Hosoda Toru, Kawanami Daiji, Takeda Norihiko, Manabe Ichiro, Suzuki Toru, Maemura Koji, Yamazaki Tsutomu, Nagai Ryozo
    Circulation Journal 68 (Suppl.I) 589 - 589 1346-9843 2004/03
  • D Kawanami, K Maemura, N Takeda, T Harada, T Nojiri, Y Imai, Manabe, I, K Utsunomiya, R Nagai
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 314 (2) 415 - 419 0006-291X 2004/02 [Refereed][Not invited]
    Resistin is an adipocytokine which plays a role in the development of insulin resistance. In this study, we investigated the direct effect of resistin on vascular endothelial cells. Resistin induced the expression of adhesion molecules such as VCAM-1 and ICAM-1, and long pentraxin 3, a marker of inflammation. The induction of VCAM-1 by resistin was inhibited partially by pitavastatin. Moreover, the induction of VCAM-1 and ICAM-1 by resistin was inhibited by adiponectin, an adipocytokine that improves insulin resistance. Taken together, these results suggest that the balance in the concentrations of adipocytokines such as resistin and adiponectin determines the inflammation status of vasculature, and in turn the progress of atherosclerosis. (C) 2003 Elsevier Inc. All rights reserved.
  • T Kawamoto, M Noshiro, F Sato, K Maemura, N Takeda, R Nagai, T Iwata, K Fujimoto, M Furukawa, K Miyazaki, S Honma, K Honma, Y Kato
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 313 (1) 117 - 124 0006-291X 2004/01 [Refereed][Not invited]
    An autofeedback loop associated with transcription of clock gene(s), Per(s), is generally accepted as the molecular machinery of circadian rhythm generation, in which CLOCK/BMAL act as positive regulators and PER/CRY as negative ones. We show here an autofeedback loop of Dec1 encoding a basic helix-loop-helix transcription factor: CLOCK/BMAL increased the promoter activity of Dec1, and DEC1 and DEC2 as well as PERs and CRYs suppressed the induced expression. Three CACGTG E-boxes are responsible for both the activation and the suppression of Dec1 transcription. Forced expression of Clock/Bmal increased endogenous Dec1 mRNA level, and overexpression of Dec1 resulted in suppression of Dec2, Per2, and Dbp expression. The level of Dec1 expression in the heart of Clock/Clock mutant mice was continuously low throughout the day. These findings suggest that Dec1 is positively regulated by CLOCK/BMAL and is involved in circadian rhythm regulation by suppressing CLOCK/BMAL-induced gene expression. The autofeedback loop of Dec1 may be interlocked with the core feedback loop of Per in some situations. (C) 2003 Elsevier Inc. All rights reserved.
  • YZ Zou, WD Zhu, M Sakamoto, YJ Qin, H Akazawa, H Toko, M Mizukami, N Takeda, T Minamino, H Takano, T Nagai, A Nakai, Komuro, I
    CIRCULATION 108 (24) 3024 - 3030 0009-7322 2003/12 [Refereed][Not invited]
    Background - Because cardiomyocyte death causes heart failure, it is important to find the molecules that protect cardiomyocytes from death. The death trap is a useful method to identify cell-protective genes. Methods and Results - In this study, we isolated the heat shock transcription factor 1 (HSF1) as a protective molecule by the death trap method. Cell death induced by hydrogen peroxide was prevented by overexpression of HSF1 in COS7 cells. Thermal preconditioning at 42 degreesC for 60 minutes activated HSF1, which played a critical role in survival of cardiomyocytes from oxidative stress. In the heart of transgenic mice overexpressing a constitutively active form of HSF1, ischemia followed by reperfusion-induced ST-segment elevation in ECG was recovered faster, infarct size was smaller, and cardiomyocyte death was less than wild-type mice. Protein kinase B/Akt was more strongly activated, whereas Jun N-terminal kinase and caspase 3 were less activated in transgenic hearts than wild-type ones. Conclusions - These results suggest that HSF1 protects cardiomyocytes from death at least in part through activation of Akt and inactivation of Jun N-terminal kinase and caspase 3.
  • T Harada, H Morita, Y Imai, D Hayashi, N Takeda, K Maemura, Y Yazaki, R Nagai
    ANGIOLOGY 54 (3) 377 - 381 0003-3197 2003/05 [Refereed][Not invited]
    Deficiency of protein S causes potential problems of thrombosis. Cases of familial venous thrombosis due to deficiency of protein S were presented. First, an 85-year-old woman had pulmonary thromboembolism due to left deep femoral venous thrombosis, which might be triggered by leg fracture and the long-term treatment with a plaster cast. Next, her 29-year-old granddaughter had episodes of recurrent venous thrombosis in her legs and arms, which might be triggered by the treatment with a plaster cast and abortion. In the latter part, the aspects of risks for thromboembolism, potential problems in gestational period, and an advisability of thromboprophylaxis in patients with deficiency of protein S are described.
  • Imai Yasushi, Taketani Tsuyoshi, Maemura Koji, Hayashi Doubun, Harada Tomohiro, Takeda Norihiko, Takamoto Shinichi, Yamazaki Tsutomu, Nagai Ryozo
    Circulation Journal 67 (Suppl.I) 114 - 114 1346-9843 2003/03
  • Y Hiroi, T Nakao, N Tsuchiya, N Takeda, K Maemura, F Nakamura, M Ohno, Y Hirata, R Nagai
    JAPANESE HEART JOURNAL 44 (1) 139 - 144 0021-4868 2003/01 [Refereed][Not invited]
    A 74 year-old Japanese woman, who had suffered from Lambert-Eaton myasthenic syndrome (LEMS), Sjoegren's syndrome, and discoid lupus erythematosus for 10 years and had been successfully controlled by 3,4-diamitiopyridine and prednisolone, began to suffer from chest discomfort at night. Stress-induced myocardial ischemia in the left ventricular anterior septum was detected by thallium-201 scintigraphy. After diltiazem was prescribed, she began to feel systemic malaise and weakness in both thighs. She stopped taking diltiazem and the symptoms improved. Coronary angiography revealed 75% stenosis with calcification in the middle of the left anterior descending artery. After atherectomy with a lotablator and coronary stenting, diltiazem was prescribed. She felt malaise again, but continued taking diltiazem. After three months a follow-up coronary angiography showed no restenosis in the lesion and diltiazem was stopped. The weakness and malaise disappeared and her muscle strength recovered. LEMS is an autoimmune disorder of peripheral cholinergic transmission in which autoantibodies to the presynaptic P/Q-type voltage-gated calcium channels (VGCC) decrease the release of acetylcholine at the neuromuscular junction resulting in muscle weakness. P/Q-type VGCC regulates most of the neurotransmitter release and L-type VGCC regulates the remainder. L-type VGCC blockers are thought to have little effect on the neuromuscular junction, but they should be used very carefully, even in the remission stage of LEMS, because of preexisting neuromuscular blocking in transmission.
  • N Takeda, Yokoyama, I, Y Hiroi, M Sakata, T Harada, F Nakamura, Y Murakawa, R Nagai
    CIRCULATION 105 (9) 1144 - 1145 0009-7322 2002/03 [Refereed][Not invited]
  • Lambert-Eaton症候群がジルチアゼムにより悪化し,中止により改善した一症例
    中尾 倫子, 廣井 透雄, 武田 憲彦, 前村 浩二, 松崎 弦, 西村 剛, 中村 文隆, 大野 実, 平田 恭信, 永井 良三
    日本内科学会関東地方会 日本内科学会-関東地方会 495回 19 - 19 2001/11
  • 睡眠時無呼吸症候群を合併した心不全の一例
    中澤 学, 武田 憲彦, 江藤 陽子, 園田 誠, 村田 一郎, 中村 文隆, 大野 実, 平田 恭信, 永井 良三, 大賀 栄次郎
    日本内科学会関東地方会 日本内科学会-関東地方会 492回 31 - 31 2001/07
  • N Takeda, K Kikuchi, R Asano, T Harada, K Totsuka, T Sumiyoshi, T Uchiyama, S Hosoda
    SCANDINAVIAN JOURNAL OF INFECTIOUS DISEASES 33 (12) 927 - 928 0036-5548 2001 [Refereed][Not invited]
    Human infection with Streptococcus canis is extremely rare. We describe herein a case of septicemia with cellulitis caused by S. canis in a 75-y-old woman, which developed 2 weeks after a dog bite. Macrorestriction analysis with pulsed-field gel electrophoresis demonstrated that the organism had been transmitted by means of a dog bite to her hand.


  • 倉田里穂, 原田将光, 砂河孝行, 仙波宏章, 武田憲彦, 前村浩二, 米澤朋  月刊Precision Medicine  4-  (8)  2021
  • 熊谷飛鳥, 熊谷飛鳥, 倉田里穂, 尾崎惠一, 砂河孝行, 仙波宏章, 武田憲彦, 前村浩二, 米澤朋  Bio Clinica  34-  (9)  959  -963  2019/08  [Not refereed][Not invited]
  • 圧負荷後心臓リモデリングにおけるマクロファージ低酸素シグナルの役割
    安部 元, 武田 憲彦, 砂河 孝行, 仙波 宏章, 相馬 桂, 小山 雄広, 和氣 正樹, 加藤 愛巳, 中釜 悠, 佐藤 達之, 真鍋 一郎, 小室 一成  血管  41-  (1)  35  -35  2018/01  [Not refereed][Not invited]
  • マクロファージ微小環境適応における転写制御機構
    砂河 孝行, 武田 憲彦, 仙波 宏章, 安部 元, 相馬 桂, 和氣 正樹, 加藤 愛巳, 森岡 勝樹, 魏 碩俣, 前村 浩二  血管  41-  (1)  45  -45  2018/01  [Not refereed][Not invited]
  • 藤田知子, 廣田泰, 松本玲央奈, 武田憲彦, 藤田英俊, 原口広史, 松尾光徳, 平岡毅大, 田中智基, 赤枝俊, 大須賀穣, 藤井知行  日本生化学会大会(Web)  90th-  ROMBUNNO.4P1T12‐15(3P‐0876) (WEB ONLY)  -15(3P  2017/12  [Not refereed][Not invited]
  • 松本玲央奈, 廣田泰, 藤田知子, 伊賀上翔太, 田中智基, 平岡毅大, 松尾光徳, 原口広史, 赤枝俊, 武田憲彦, 大須賀穣, 藤井知行  日本生殖医学会雑誌  62-  (4)  387  -387  2017/10  [Not refereed][Not invited]
  • 松本玲央奈, 廣田泰, 藤田知子, 伊賀上翔太, 田中智基, 平岡毅大, 松尾光徳, 原口広史, 江頭真宏, 赤枝俊, 武田憲彦, 大須賀穣, 藤井知行  日本生殖医学会雑誌  61-  (4)  335  -335  2016/10  [Not refereed][Not invited]
  • 肥満高血圧の新たな病態修飾因子 圧負荷後心臓リモデリングにおけるマクロファージ低酸素シグナルの役割
    安部 元, 武田 憲彦, 砂河 孝行, 仙波 宏章, 相馬 桂, 小山 雄広, 和氣 正樹, 加藤 愛巳, 中釜 悠, 真鍋 一郎, 永井 良三, 小室 一成  日本高血圧学会総会プログラム・抄録集  39回-  269  -269  2016/09  [Not refereed][Not invited]
  • 心臓リモデリングにおけるマクロファージ低酸素シグナルの役割
    安部 元, 武田 憲彦, 砂河 孝行, 仙波 宏章, 相馬 桂, 小山 雄広, 和氣 正樹, 加藤 愛巳, 中釜 悠, 真鍋 一郎, 永井 良三, 小室 一成  日本生化学会大会プログラム・講演要旨集  89回-  [1T07  -284)]  2016/09  [Not refereed][Not invited]
  • マクロファージ微小環境適応における転写制御機構
    砂河 孝行, 武田 憲彦, 仙波 宏章, 小山 雄広, 安部 元, 相馬 桂, 和氣 正樹, 加藤 愛巳, 森岡 正樹, 真鍋 一郎, 前村 浩二, 永井 良三, 小室 一成  日本生化学会大会プログラム・講演要旨集  89回-  [1P  -031]  2016/09  [Not refereed][Not invited]
  • HIF-1α-PDK1経路を介した代謝リプログラミングによるマクロファージ遊走制御
    仙波 宏章, 武田 憲彦, 砂河 孝行, 杉浦 悠毅, 本多 久楽々, 和氣 正樹, 宮沢 英延, 山口 良文, 三浦 正幸, 安部 元, 相馬 桂, 小山 雄広, 加藤 愛己, 真鍋 一郎, 永井 良三, 山下 武志, 小室 一成  日本生化学会大会プログラム・講演要旨集  89回-  [1P  -033]  2016/09  [Not refereed][Not invited]
  • K. Soma, N. Takeda, T. Isagawa, H. Abe, H. Semba, K. Koyama, M. Wake, M. Katoh, I. Manabe, R. Nagai, I. Komuro  EUROPEAN HEART JOURNAL  37-  907  -908  2016/08  [Not refereed][Not invited]
  • Leona Matsumoto, Yasushi Hirota, Tomoko Saito-Fujita, Hirofumi Haraguchi, Mahiro Egashira, Mitsunori Matsuo, Takehiro Hiraoka, Tomoki Tanaka, Norihiko Takeda, Yutaka Osuga, Tomoyuki Fujii  JOURNAL OF REPRODUCTIVE IMMUNOLOGY  112-  124  -124  2015/11  [Not refereed][Not invited]
  • Matsumoto L, Hirota Y, Osuga Y, Fujii T  Reprod Immunol Biol  30-  (1-2)  98  -98  2015/11  [Not refereed][Not invited]
  • 松本玲央奈, 廣田泰, 藤田知子, 原口広史, 江頭真宏, 松尾光徳, 平岡毅大, 田中智基, 武田憲彦, 大須賀穣, 藤井知行  日本内分泌学会雑誌  91-  (2)  601  -601  2015/09  [Not refereed][Not invited]
  • K. Soma, N. Takeda, T. Isagawa, H. Abe, H. Semba, K. Koyama, M. Wake, I. Manabe, R. Nagai, I. Komuro  EUROPEAN HEART JOURNAL  36-  868  -868  2015/08  [Not refereed][Not invited]
  • 圧負荷後心臓リモデリングにおけるマクロファージ低酸素シグナルの役割
    安部 元, 武田 憲彦, 砂河 孝行, 仙波 宏章, 相馬 桂, 小山 雄広, 和氣 正樹, 真鍋 一郎, 永井 良三, 小室 一成  日本臨床分子医学会学術総会プログラム・抄録集  52回-  73  -73  2015/04  [Not refereed][Not invited]
  • H. Semba, N. Takeda, T. Isagawa, M. Morioka, H. Abe, K. Soma, K. Koyama, I. Manabe, R. Nagai, I. Komuro  EUROPEAN HEART JOURNAL  35-  1024  -1024  2014/09  [Not refereed][Not invited]
  • 圧負荷後心臓リモデリングにおけるマクロファージ低酸素シグナルの役割
    安部 元, 武田 憲彦, 砂河 孝行, 仙波 宏章, 相馬 桂, 小山 雄広, 真鍋 一郎, 永井 良三, 小室 一成  適応医学  18-  (1)  18  -18  2014/06  [Not refereed][Not invited]
  • マクロファージ代謝リプログラミングにおける細胞内低酸素センサー
    武田 憲彦, 仙波 宏章, 杉浦 悠毅, 砂河 孝行, 安部 元, 相馬 桂, 小山 雄広, 永井 良三, 真鍋 一郎, 小室 一成  適応医学  18-  (1)  20  -20  2014/06  [Not refereed][Not invited]
  • 心臓リモデリングにおけるマクロファージ低酸素シグナルの役割
    安部 元, 武田 憲彦, 砂河 孝行, 仙波 宏章, 相馬 桂, 小山 雄広, 真鍋 一郎, 永井 良三, 小室 一成  日本臨床分子医学会学術総会プログラム・抄録集  51回-  64  -64  2014/04  [Not refereed][Not invited]
  • Hajime Abe, Norihiko Takeda, Hiroaki Semba, Soma Katura, Ichiro Manabe, Ryozo Nagai  CIRCULATION  126-  (21)  2012/11  [Not refereed][Not invited]
  • エピジェネテイクスを介するマクロファージ慢性ストレス応答の制御機構
    仙波 宏章, 武田 憲彦, 砂河 孝行, 森岡 勝樹, 安部 元, 相馬 桂, 真鍋 一郎, 永井 良三  日本内分泌学会雑誌  88-  (2)  837  -837  2012/09  [Not refereed][Not invited]
  • Naoko Kato, Koichiro Kinugawa, Taro Shiga, Masaru Hatano, Norihiko Takeda, Yasushi Imai, Masafumi Watanabe, Atsushi Yao, Yasunobu Hirata, Ryozo Nagai  JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY  59-  (13)  E1035  -E1035  2012/03  [Not refereed][Not invited]
  • Norihiko Takeda, Hajime Abe, Hiroaki Senba, Randall Johnson, Ichiro Manabe, Ryozo Nagai  CIRCULATION  124-  (21)  2011/11  [Not refereed][Not invited]
  • 武田 憲彦, 前村 浩二  Anti-aging medicine  6-  (6)  872  -876  2010/12  [Not refereed][Not invited]
  • アンチエイジングのバイオロジー 老化と時計遺伝子
    武田憲彦, 前村浩二  日本抗加齢医学会雑誌 アンチ・エイジング医学  6-  (6)  84  -88  2010  [Not refereed][Not invited]
  • 特集 生体リズム研究の最近の進歩:心血管系を調節 する時計機構 時計機構に連関するHIF遺伝子の役割.
    武田憲彦, 前村浩二  循環器内科  68-  (5)  482  -488  2010  [Not refereed][Not invited]
  • RASのサーカディアンリズム
    武田憲彦, 前村浩二  Progress in Medicine  26-  3179  -3184  2006  [Not refereed][Not invited]
  • 時計遺伝子による心臓イオンチャネルの発現制御
    渡辺英一, 童 茂清, 石黒(長幡)操, 山本直樹, 荒川友晴, 祖父江嘉洋, 菱田 仁, 前村浩二, 武田憲彦, 永井良三, 児玉逸雄  Therapeutic Research  27-  94  -95  2006  [Not refereed][Not invited]
  • T Harada, K Maemura, N Takeda, Y Imai, T Saito, R Nagai  JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY  39-  (6)  1007  -1008  2005/12  [Not refereed][Not invited]
  • T Harada, Y Imai, N Takeda, D Kawanami, T Nojiri, T Saito, K Maemura  CIRCULATION  112-  (17)  U108  -U109  2005/10  [Not refereed][Not invited]
  • N Takeda, S Horie, Y Imai, T Harada, D Kawanami, T Saito, T Nojiri, S Saegusa, K Oishi, N Ishida, K Maemura  CIRCULATION  112-  (17)  U193  -U193  2005/10  [Not refereed][Not invited]
  • レジスチンによる血管内皮機能調節
    川浪 大治, 宇都宮 一典, 前村 浩二, 三枝 誠一郎, 武田 憲彦, 原田 智浩, 野尻 剛史, 斉藤 哲也, 今井 靖, 田嶼 尚子, 永井 良三  糖尿病合併症  19-  (Suppl.1)  75  -75  2005/09  [Not refereed][Not invited]
  • PlGF遺伝子の発現調節の解析
    齊藤 哲也, 前村 浩二, 武田 憲彦, 川浪 大治, 原田 智浩, 野尻 剛史, 今井 靖, 永井 良三  日本動脈硬化学会総会プログラム・抄録集  37回-  240  -240  2005/07  [Not refereed][Not invited]
  • Maemura Koji, Takeda Norihiko, Nagai Ryozo  Proceedings of Annual Meeting of the Physiological Society of Japan  2005-  (0)  S25  -S25  2005  [Not refereed][Not invited]
    Cardiovascular function and frequencies of onset of cardiovascular diseases show circadian oscillation. Furthermore, cultured vascular endothelial cells and cardiomyocytes showed circadian oscillation of clock genes expression, suggesting the existence of the peripheral clock in cardiovascular systems. To elucidate the functional relevance of the peripheral clock in cardiovascular system, we first tried to identify the target genes of the peripheral clock. We demonstrated that PAI-1 mRNA levels exhibited circadian variation and that CLOCK and BMAL increased PAI-1gene expression mediated through the E-box sites. The circadian oscillation of PAI-1 gene expression is responsible for the decreased fibrinolytic activity that attributes to the morning onset of myocardial infarction. We further identified several target genes of the peripheral clock by cDNA microarray analysis using RNA from vascular endothelial cells. We are analyzing the function of these genes in cardiovascular system. We next generated transgenic mice in which Cry1, a negative regulator of the molecular clock, is overexpressed specifically in vascular endothelial cells to analyze the function of the peripheral clock separately from the central clock. Taken together, these results suggest that cardiovascular systems have their own peripheral clocks and at least in part, they may regulate the circadian oscillation of cardiovascular function directly. These results potentially provide a molecular basis for the circadian variation of cardiovascular function and novel strategies for the treatment of cardiovascular diseases. <b>[Jpn J Physiol 55 Suppl:S25 (2005)]</b>
  • N Takeda, Y Imai, D Kawanami, T Harada, T Nojiri, T Saito, Manabe, I, K Maemura  CIRCULATION  110-  (17)  224  -224  2004/10  [Not refereed][Not invited]
  • 循環器疾患の好発時間—時間遺伝子はどのように影響するかー
    川浪大治, 武田憲彦, 前村浩二  Medical Practice  21-  284  -285  2004  [Not refereed][Not invited]
  • 転写因子HIFの心血管リモデリングにおける役割と治療への応用
    前村浩二, 武田憲彦, 原田智浩, 永井良三  診療と新薬  41-  869  -871  2004  [Not refereed][Not invited]
  • 心臓血管外科の際に得られる切除標本を活用した動脈硬化性疾患の病態解析
    今井 靖, 竹谷 剛, 前村 浩二, 原田 智浩, 武田 憲彦, 川浪 大治, 山崎 力, 高本 眞一, 永井 良三  血栓と循環  11-  (4)  375  -376  2003/12  [Not refereed][Not invited]
  • N Takeda, K Maemura, Y Imai, D Kawanami, T Harada, T Nojiri, R Nagai  CIRCULATION  108-  (17)  113  -113  2003/10  [Not refereed][Not invited]
  • D Kawanami, K Maemura, N Takeda, T Harada, T Nojiri, Y Imai, R Nagai  CIRCULATION  108-  (17)  300  -301  2003/10  [Not refereed][Not invited]
  • K Maemura, N Takeda, H Morita, Y Imai, T Harada, T Nojiri, R Nagai  ATHEROSCLEROSIS SUPPLEMENTS  4-  (2)  58  -59  2003/09  [Not refereed][Not invited]
  • N Takeda, K Maemura, Y Imai, T Harada, D Kawanami, T Nojiri, Manabe, I, R Nagai  ATHEROSCLEROSIS SUPPLEMENTS  4-  (2)  204  -204  2003/09  [Not refereed][Not invited]
  • D Kawanami, K Maemura, N Takeda, T Harada, T Nojiri, Y Imai, R Nagai  ATHEROSCLEROSIS SUPPLEMENTS  4-  (2)  331  -331  2003/09  [Not refereed][Not invited]
  • 前村浩二, 武田憲彦, 森田啓行, 今井靖, 永井良三  日本時間生物学会会誌  9-  (1)  11  -15  2003/05  [Not refereed][Not invited]
  • N Takeda, K Maemura, Y Imai, T Harada, T Nojiri, R Nagai  CIRCULATION  106-  (19)  215  -215  2002/11  [Not refereed][Not invited]
  • N Takeda, Y Imai, T Harada, T Nojiri, K Maemura  CIRCULATION  106-  (19)  107  -107  2002/11  [Not refereed][Not invited]
  • 前村 浩二, 武田 憲彦, 森田 啓行, 今井 靖, 永井 良三  日本時間生物学会会誌: Journal of Chronobiology  8-  (2)  2002/10  [Not refereed][Not invited]
  • 【わが国における冠動脈インターベンションの現況】 冠動脈インターベンションを取り巻く最近のトピックス 21世紀の冠動脈インターベンションの動向 冠動脈インターベンションにおいて費用対効果をどうとらえるか
    武田 憲彦, 山崎 力, 浅野 竜太, 住吉 徹哉  Cardiac Practice  13-  (2)  213  -216  2002/04  [Not refereed][Not invited]

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