研究者業績
  1. 研究者検索結果一覧
  2. 永井 良三

永井 良三

ナガイ リョウゾウ  (Ryozo Nagai)

基本情報

所属
自治医科大学 自治医科大学 学長
学位
博士(医学)
J-GLOBAL ID
200901024033893870
researchmap会員ID
1000190318

研究キーワード

 4

研究分野

 1

委員歴

 5

受賞

 7
もっとみる

論文

 969
  • Yu Yoshiki, Yukio Ozaki, Mitsuru Abe, Tevfik F Ismail, Hiroshi Takahashi, Masaharu Akao, Hideki Kawai, Takashi Muramatsu, Masahide Harada, Masaya Ohta, Yosuke Hashimoto, Yuichiro Shiki, Masayuki Koshikawa, Keiichi Miyajima, Hidemaro Takatsu, Yudai Niwa, Naoyuki Kawashima, Reina Ozaki, Naotake Tsuboi, Satoshi Iimuro, Hiroshi Iwata, Ichiro Sakuma, Yoshihisa Nakagawa, Kiyoshi Hibi, Takafumi Hiro, Yoshihiro Fukumoto, Seiji Hokimoto, Katsumi Miyauchi, Hisao Ogawa, Hiroyuki Daida, Hiroaki Shimokawa, Hideo Izawa, Takeshi Kimura, Ryozo Nagai
    Journal of the American Heart Association 14(2) e034627 2025年1月21日  
    BACKGROUND: The effect of worsening renal function and baseline chronic kidney disease (CKD) on outcomes in patients with chronic coronary syndrome in the setting of optimal medical therapy remains unknown. METHODS AND RESULTS: The REAL-CAD (Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy With Pitavastatin in Coronary Artery Disease) study is a prospective, multicenter, randomized trial of high-dose (pitavastatin 4 mg/day) or low-dose (pitavastatin 1 mg/day) statin therapy in 12 118 patients with chronic coronary syndrome. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, stroke, or unstable angina requiring hospitalization (major adverse cardiac and cerebral events [MACCE]). CKD was defined as an estimated glomerular filtration rate [eGFR] <60 mL/min per 1.73 m2. WRF was defined as a decrease in eGFR ≥20% in the initial year; borderline renal function was an annual decrease of 0%<eGFR<20%, and stable renal function was no decrease. Of 12 118 patients, 4340 had baseline CKD and 7778 did not. The rate of MACCE at 5 years was significantly lower in those without (5.5%) versus with CKD (9.5%) (P<0.0001). After excluding 1247 patients who had MACCE, were censored, or missing eGFR within 1 year, 10 871 patients were included. Of these, 3885 were baseline CKD and the remaining 6986 did not have baseline CKD. Of the 10 871 patients, 577 patients had WRF, 6014 patients showed borderline renal function, and the remaining 4280 patients maintained stable renal function. In patients with CKD, WRF was an independent predictor for MACCE at 4 years as compared with stable renal function (hazard ratio [HR]: 1.67; [95% CI, 1.03-2.73; P=0.039]). In patients without CKD, borderline renal function was a significant predictor for MACCE at 4 years compared with stable renal function (HR: 1.40 [95% CI, 1.03-1.91; P=0.032]). CONCLUSIONS: Baseline CKD was an independent predictor for MACCE in patients with CCS. WRF was a significant predictor for MACCE in patients with CKD. Because borderline renal function was an independent predictor for MACCE even in patients without CKD, mild-to-moderate annual declines of eGFR should be carefully monitored (NCT01042730). REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT01042730.
  • Kosuke Nagaoka, Natsuka Kimura, Satoru Inoda, Takuya Takayama, Yusuke Arai, Yasuo Yanagi, Takashi Shimada, Ryozo Nagai, Hidenori Takahashi, Kenichi Aizawa
    International Journal of Molecular Sciences 26(2) 556-556 2025年1月10日  査読有り
  • Yasuhiro Hitomi, Yasushi Imai, Masanari Kuwabara, Yusuke Oba, Tomoyuki Kabutoya, Kazuomi Kario, Hisaki Makimoto, Takahide Kohro, Eiichi Shiraki, Naoyuki Akashi, Hideo Fujita, Tetsuya Matoba, Yoshihiro Miyamoto, Arihiro Kiyosue, Kenichi Tsujita, Masaharu Nakayama, Ryozo Nagai
    IJC Heart &amp; Vasculature 54 101507-101507 2024年10月  
  • Yusuke Oba, Tomoyuki Kabutoya, Takahide Kohro, Yasushi Imai, Kazuomi Kario, Hisahiko Sato, Kotaro Nochioka, Masaharu Nakayama, Naoyuki Akashi, Hideo Fujita, Yoshiko Mizuno, Arihiro Kiyosue, Takamasa Iwai, Yoshihiro Miyamoto, Yasuhiro Nakano, Masanobu Ishii, Taishi Nakamura, Kenichi Tsujita, Tetsuya Matoba, Ryozo Nagai
    Hypertension research : official journal of the Japanese Society of Hypertension 2024年9月19日  
    The Japanese Society of Hypertension have established a blood pressure (BP) target of 130/80 mmHg for patients with coronary artery disease (CAD). We evaluated the data of 8793 CAD patients in the Clinical Deep Data Accumulation System database who underwent cardiac catheterization at six university hospitals and the National Cerebral and Cardiovascular Center (average age 70 ± 11 years, 78% male, 43% with acute coronary syndrome [ACS]). Patients were divided into two groups based on whether or not they achieved the guideline-recommended BP of <130/80 mmHg. We analyzed the relationship between BP classification and major adverse cardiac and cerebral event (MACCE) separately in two groups: those with ACS and those with chronic coronary syndrome (CCS). During an average follow-up period of 33 months, 710 MACCEs occurred. A BP below 130/80 mmHg was associated with fewer MACCEs in both the overall (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.70-1.00, p = 0.048) and the ACS group (HR 0.67, 95%CI 0.51-0.88, p = 0.003). In particular, stroke events were also lower among those with a BP below 130/80 mmHg in both the overall (HR 0.69, 95%CI 0.53-0.90, p = 0.006) and ACS groups (HR 0.44, 95%CI 0.30-0.67, p < 0.001). In conclusion, the achievement of BP guidelines was associated with improved outcomes in CAD patients, particularly in reducing stroke risk among those with ACS.
  • 西田 翔, 石間 環, 木村 夏花, 岩見 大基, 永井 良三, 今井 靖, 相澤 健一
    移植 59(総会臨時) 292-292 2024年9月  
もっとみる

MISC

 1923
  • Ichiro Manabe, Takayuki Shindo, Ryozo Nagai
    Circulation research 91(12) 1103-13 2002年12月13日  査読有り
    Structural remodeling of the ventricular wall is a key determinant of clinical outcome in heart disease. Such remodeling involves the production and destruction of extracellular matrix proteins, cell proliferation and migration, and apoptotic and necrotic cell death. Cardiac fibroblasts are crucially involved in these processes, producing growth factors and cytokines that act as autocrine and paracrine factors, as well as extracellular matrix proteins and proteinases. Recent studies have shown that the interactions between cardiac fibroblasts and cardiomyocytes are essential for the progression of cardiac remodeling. This review addresses the functional role played by cardiac fibroblasts and the molecular mechanisms that govern their activity during cardiac hypertrophy and remodeling. A particular focus is the recent progress toward our understanding of the transcriptional regulatory mechanisms involved.
  • Kuniko Terasawa, Toshiaki Nakajima, Haruko Iida, Kuniaki Iwasawa, Hitoshi Oonuma, Taisuke Jo, Toshihiro Morita, Fumitaka Nakamura, Yoshiharu Fujimori, Teruhiko Toyo-oka, Ryozo Nagai
    Circulation 106(24) 3111-9 2002年12月10日  査読有り
    BACKGROUND: The effects of lysophosphatidylcholine (LPC) on electrophysiological activities and intracellular Ca2+ concentration ([Ca2+]i) were investigated in coronary arterial smooth muscle cells (CASMCs). METHODS AND RESULTS: The patch clamp techniques and Ca2+ measurements were applied to cultured rabbit CASMCs. The membrane potential was -46.0+/-5.0 mV, and LPC depolarized it. Replacement of extracellular Na+ with NMDG+ hyperpolarized the membrane and antagonized the depolarizing effects of LPC. In Na+-, K+-, or Cs+-containing solution, the voltage-independent background current with reversal potential (E(r)) of approximately +0 mV was observed. Removal of Cl- failed to affect it. When extracellular cations were replaced by NMDG+, E(r) was shifted to negative potentials. La3+ and Gd3+ abolished the background current, but nicardipine and verapamil did not inhibit it. In Na+-containing solution, LPC induced a voltage-independent current with E(r) of approximately +0 mV concentration-dependently. Similar current was recorded in K+- and Cs+-containing solution. La3+ and Gd3+ inhibited LPC-induced current, but nicardipine and verapamil did not inhibit it. In cell-attached configurations, single-channel activities with single-channel conductance of approximately 32pS were observed when patch pipettes were filled with LPC. LPC increased [Ca2+]i as the result of Ca2+ influx, and La3+ completely antagonized it. CONCLUSIONS: These results suggest that (1) nonselective cation current (I(NSC)) contributes to form membrane potentials of CASMCs and (2) LPC activates I(NSC), resulting in an increase of [Ca2+]i. Thus, LPC may affect CASMC tone under various pathophysiological conditions such as ischemia.
  • N Takeda, K Maemura, Y Imai, T Harada, T Nojiri, R Nagai
    CIRCULATION 106(19) 215-215 2002年11月  
  • Y Saito, T Nakamura, M Sato, H Kanai, Y Ohyama, M Kurabayashi, M Kuro-o, Y Nabeshima, R Nagai
    CIRCULATION 106(19) 182-182 2002年11月  
  • T Suzuki, S Miyamoto, K Aizawa, S Muto, M Horikoshi, R Nagai
    CIRCULATION 106(19) 165-166 2002年11月  
  • S Muto, T Suzuki, K Aizawa, S Miyamoto, R Nagai, M Horikoshi
    CIRCULATION 106(19) 288-289 2002年11月  
  • G Nishimura, Manabe, I, K Fujiu, K Tsushima, Y Oishi, R Nagai
    CIRCULATION 106(19) 137-137 2002年11月  
  • T Yamauchi, J Kamon, Y Minokoshi, Y Ito, H Waki, S Uchida, S Yamashita, M Noda, S Kita, K Ueki, K Eto, Y Akanuma, P Froguel, F Foufelle, P Ferre, D Carling, S Kimura, R Nagai, B B Kahn, T Kadowaki
    Nature medicine 8(11) 1288-95 2002年11月  査読有り
    Adiponectin (Ad) is a hormone secreted by adipocytes that regulates energy homeostasis and glucose and lipid metabolism. However, the signaling pathways that mediate the metabolic effects of Ad remain poorly identified. Here we show that phosphorylation and activation of the 5'-AMP-activated protein kinase (AMPK) are stimulated with globular and full-length Ad in skeletal muscle and only with full-length Ad in the liver. In parallel with its activation of AMPK, Ad stimulates phosphorylation of acetyl coenzyme A carboxylase (ACC), fatty-acid oxidation, glucose uptake and lactate production in myocytes, phosphorylation of ACC and reduction of molecules involved in gluconeogenesis in the liver, and reduction of glucose levels in vivo. Blocking AMPK activation by dominant-negative mutant inhibits each of these effects, indicating that stimulation of glucose utilization and fatty-acid oxidation by Ad occurs through activation of AMPK. Our data may provide a novel paradigm that an adipocyte-derived antidiabetic hormone, Ad, activates AMPK, thereby directly regulating glucose metabolism and insulin sensitivity in vitro and in vivo.
  • K Monzen, WD Zhu, H Kasai, Y Hiroi, T Hosoda, H Akazawa, YZ Zou, D Hayashi, T Yamazaki, R Nagai, Komuro, I
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 298(4) 493-500 2002年11月  
    A homeobox-containing transcription factor Csx/Nkx2-5 is an important regulator of cardiac development. Many different human CSX/NKX2-5 mutations have been reported to cause congenital heart disease. We here examined the effects of three representative CSX/NKX2-5 mutations on cardiomyocyte differentiation and death with the use of the P19CL6 cardiomyogenic cell. lines. Stable overexpression of wild-type CSX/NKX2-5 enhanced expression of cardiac-specific genes such as MEF2C and MLC2upsilon, the promoter activity of the atrial natriuretic peptide gene, and the terminal differentiation of P19CL6 into cardiomyocytes, while all CSX/NKX2-5 mutants attenuated them by different degrees. When exposed to H2O2 or cultured without change of the medium, many differentiated P19CL6 cells overexpressing the mutants, especially the mutant which lacks the carboxyl terminal region just after the homeodomain, were dead, while most of the cells overexpressing wild-type CSX/NKX2-5 survived. Overexpression of the carboxyl terminus-deleted mutant down-regulated expression of an anti-apoptotic protein Bcl-x(L) and up-regulated that of a proapoptotic protein CAS, while in the cells overexpressing wild-type CSX/NKX2-5, expression of a pro-apoptotic protein RIP was reduced. Furthermore, overexpression of wild-type CSX/NKX2-5 decreased the number of H2O2-induced TUNEL-positive cultured cardiomyocytes of neonatal rats, whereas overexpression of the mutants enhanced it. These results suggest that Csx/Nkx2-5 not only regulates expression of cardiac-specific genes but protects cardiomyocytes from stresses and that cell death may be another cause for the cardiac defects induced by human CSX/NKX2-5 mutations. (C) 2002 Elsevier Science (USA). All rights reserved.
  • Tomoko Aoki-Nagase, Takahide Nagase, Yoshio Oh-Hashi, Takayuki Shindo, Yukiko Kurihara, Yasuhiro Yamaguchi, Hiroshi Yamamoto, Tetsuji Tomita, Eijiro Ohga, Ryozo Nagai, Hiroki Kurihara, Yasuyoshi Ouchi
    American journal of physiology. Lung cellular and molecular physiology 283(5) L963-70-L970 2002年11月  査読有り
    Bronchial hyperresponsiveness and eosinophilia are major characteristics of asthma. Calcitonin gene-related peptide (CGRP) is a neuropeptide that has various biological actions. In the present study, we questioned whether CGRP might have pathophysiological roles in airway hyperresponsiveness and eosinophilia in asthma. To determine the exact roles of endogenous CGRP in vivo, we chose to study antigen-induced airway responses using CGRP gene-disrupted mice. After ovalbumin sensitization and antigen challenge, we assessed airway responsiveness and measured proinflammatory mediators. In the sensitized CGRP gene-disrupted mice, antigen-induced bronchial hyperresponsiveness was significantly attenuated compared with the sensitized wild-type mice. Antigen challenge induced eosinophil infiltration in bronchoalveolar lavage fluid, whereas no differences were observed between the wild-type and CGRP-mutant mice. Antigen-induced increases in cysteinyl leukotriene production in the lung were significantly reduced in the CGRP-disrupted mice. These findings suggest that CGRP could be involved in the antigen-induced airway hyperresponsiveness, but not eosinophil infiltration, in mice. The CGRP-mutant mice may provide appropriate models to study molecular mechanisms underlying CGRP-related diseases.
  • T Shindo, Manabe, I, K Aizawa, T Suzuki, K Maemura, M Kurabayashi, R Nagai
    CIRCULATION 106(19) H-H 2002年11月  
  • 永井 良三
    臨床病理 50 3-3 2002年10月30日  
  • 小川 陽子, 井上 博睦, 佐藤 隆久, 藤本 肇, 山下 尋史, 横山 郁夫, 大野 実, 平田 恭信, 永井 良三
    Circulation journal : official journal of the Japanese Circulation Society 66 1028-1028 2002年10月20日  
  • Takeshi Natori, Masataka Sata, Miwa Washida, Yasunobu Hirata, Ryozo Nagai, Masatoshi Makuuchi
    Biochemical and biophysical research communications 297(4) 1058-61 2002年10月4日  査読有り
    Solid tumors require neovascularization for their growth. Recent evidence indicates that bone marrow-derived endothelial progenitor cells (EPCs) contribute to tumor angiogenesis. We show here that granulocyte colony-stimulating factor (G-CSF) markedly promotes growth of the colon cancer inoculated into the subcutaneous space of mice, whereas G-CSF had no effect on cancer cell proliferation in vitro. The accelerated tumor growth was associated with enhancement of neovascularization in the tumor. We found that bone marrow-derived cells participated in new blood vessel formation in tumor. Our findings suggest that G-CSF may have potential to promote tumor growth, at least in part, by stimulating angiogenesis in which bone marrow-derived EPCs play a role.
  • 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年10月1日  
  • M Matsuda, Shimomura, I, M Sata, Y Arita, M Nishida, N Maeda, M Kumada, Y Okamoto, H Nagaretani, H Nishizawa, K Kishida, R Komuro, N Ouchi, S Kihara, R Nagai, T Funahashi, Y Matsuzawa
    JOURNAL OF BIOLOGICAL CHEMISTRY 277(40) 37487-37491 2002年10月  
    Obesity is more linked to vascular disease, including atherosclerosis and restenotic change, after balloon angioplasty. The precise mechanism linking obesity and vascular disease is still unclear. Previously we have demonstrated that the plasma levels of adiponectin, an adipose-derived hormone, decreases in obese subjects, and that hypoadiponectinemia is associated to ischemic heart disease. In current the study, we investigated the in vivo role of adiponectin on the neointimal thickening after artery injury using adiponectin-deficient mice and adiponectin-producing adenovirus. Adiponectin-deficient mice showed severe neointimal thickening and increased proliferation of vascular smooth muscle cells in mechanically injured arteries. Adenovirus-mediated supplement of adiponectin attenuated neointimal proliferation. In cultured smooth muscle cells, adiponectin attenuated DNA synthesis induced by growth factors including platelet-derived growth factor, heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), basic fibroblast growth factor, and EGF and cell proliferation and migration induced by HB-EGF. In cultured endothelial cells, adiponectin attenuated HB-EGF expression stimulated by tumor necrosis factor a. The current study suggests an adipo-vascular axis, a direct link between fat and artery. A therapeutic strategy to increase plasma adiponectin should be useful in preventing vascular restenosis after angioplasty.
  • H Kaneda, M Ohno, J Taguchi, M Togo, H Hashimoto, K Ogasawara, T Aizawa, N Ishizaka, R Nagai
    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 22(10) 1680-1685 2002年10月  
    Objective-Heme oxygenase (HO) is important in the defense against oxidative stress and as a factor in an antiatherogenic mechanism. Compared with long (GT)(n) repeats, short (GT)(n) repeats in the human HO-1 gene promoter were shown to have higher transcriptional activity in response to oxidative stress. There is a strong link between oxidative stress and the pathogenesis of coronary artery disease (CAD). Methods and Results-We screened the allelic frequencies of (GT)(n) repeats in the HO- 1. gene promoter in 577 patients who underwent coronary angiography. Because the distribution of numbers of (GT)(n) repeats was bimodal, we divided the alleles into 2 subclasses: class S included shorter (&lt;27) repeats, and class L included longer ( &GE; 27) repeats. Multivariate logistic regression models including standard coronary risk factors revealed that the genotypes were significantly related to CAD status in hypercholesterolemic, diabetic patients or in smokers. In this study, the patients with shorter GT repeats were less likely to have CAD. Conclusions-Length polymorphism in the HO-1 gene promoter is related to CAD susceptibility in Japanese people who also have coronary risk factors such as hypercholesterolemia, diabetes, and smoking. HO-1 may play an antiatherogenic role in Japanese patients with these coronary risk factors.
  • N Ishizaka, K Saito, H Mitani, Yamazaki, I, M Sata, S Usui, Mori, I, M Ohno, R Nagai
    CIRCULATION 106(14) 1840-1846 2002年10月  
    Background-Abnormal iron deposition may cause oxidant-induced damage in various organs. We have previously reported that continuous administration of angiotensin II to rats results in an overt iron deposition in the renal tubular epithelial cells, which may have a role in angiotensin II-induced renal damage. In the present study, we investigated the role of iron in the development of cardiac injury induced by angiotensin II. Methods and Results-Angiotensin II was continuously infused to rats at a dose of 0.7 mg/kg per day for 7 consecutive days. No iron deposits were observed in the hearts of untreated rats, whereas iron deposition was seen in the cells in the subepicardial and granulation regions after angiotensin II infusion. Concomitant administration of deferoxamine, an iron chelator, significantly reduced the extent of cardiac fibrosis, which suggests that iron deposition aggravates the cardiac fibrosis induced by angiotensin II. Iron overload caused by the administration of iron-dextran resulted in an augmentation of cardiac fibrosis and the generation of neointimal cells in the coronary artery in angiotensin II-infused rats. By contrast, neointima was not formed in the cardiac vessels in norepinephrine-infused rats with iron overload. Conclusions-Cardiac iron deposition may be involved in the development of cardiac fibrosis induced by angiotensin II. In addition, iron overload may enhance the formation of neointima under conditions of increased circulating angiotensin II but not catecholamines.
  • 吹野 恵子, 鈴木 亨, 永井 良三
    最新医学 57(9) 2014-2018 2002年9月  
  • 今井 靖, 永井 良三
    内科 90(3) 570-572 2002年9月  
  • Lawrence J Saubermann, Atsushi Nakajima, Koichiro Wada, Shuping Zhao, Yasuo Terauchi, Takashi Kadowaki, Hiroyuki Aburatani, Nobuyuki Matsuhashi, Ryozo Nagai, Richard S Blumberg
    Inflammatory bowel diseases 8(5) 330-9 2002年9月  査読有り
    Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of a nuclear transcription factor family, has been previously demonstrated to have antiinflammatory activity. The effects of PPARgamma activation in the development of an immune response are less well characterized. Through evaluation of PPARgamma heterozygote mice (PPARgamma(+/-) and specific PPARgamma agonist ligand binding, we evaluated the immunologic effects of PPARgamma activation in a well-described model of colitis. Increased susceptibility to dextran sodium sulfate (DSS)-induced colitis as defined by body weights, histologic injury, and survival was observed in the PPARgamma(+/-) mice in comparison to wild-type mice. Three different PPARgamma ligands (troglitazone, pioglitazone, and rosiglitazone) demonstrated beneficial dose-related treatment effects when administered prior to the onset of colitis. However, no protection was observed when PPARgamma ligand activation occurred after the onset of colitis. The reduction in DSS-induced inflammation noted with PPARgamma ligand treatment was associated with decreased interferon-gamma and tumor necrosis factor-alpha and increased interleukin (IL)-4 and IL- 10 levels as assessed by quantitative reverse transcriptase-polymerase chain reaction. Consistent with this shift towards a T helper (Th2) cytokine dominance, PPARgamma ligand treatment stimulated increased GATA-3 expression. These results indicate that the protective effects exhibited by PPARgamma ligands in intestinal inflammation may be due to immune deviation away from Th1 and towards Th2 cytokine production.
  • Mariko Kamemori, Yoshio Ohyama, Masahiko Kurabayashi, Katumasa Takahashi, Ryozo Nagai, Nobuhiko Furuya
    Hearing research 171(1-2) 103-110 2002年9月  査読有り
    The Klotho mouse is a recently developed model that exhibits phenotypes resembling human aging. We used this model to investigate sensorineural hearing loss from the point of view that it may be considered an issue of aging. Using reverse transcription-polymerase chain reaction, Western blotting and immunohistochemical staining, we were able to confirm klotho gene transcription and protein synthesis in the kidney and inner ear. Klotho protein was mainly expressed in the stria vascularis and spiral ligament of the inner ear and in the distal convoluted tubule of the kidney, likely serving a common function in the two organs, i.e., modulating ion transport. The threshold for the auditory brainstem response was significantly higher in Klotho mice than in wild-type mice, and wave I latencies were prolonged. On the other hand, Klotho mice exhibited a normal distribution of I-IV interpeak intervals. No obvious morphological abnormalities were detected in Klotho mice, although no expression of Klotho protein was detected, and there was an apparent hearing disorder. Taken together, these findings suggest that by contributing to the maintenance ion homeostasis in the endolymph, Klotho protein serves as a key mediator of auditory function.
  • Etsu Suzuki, Hiroaki Nishimatsu, Daisuke Nagata, Hiroshi Satonaka, Atsuo Goto, Masao Omata, Toshiro Fujita, Ryozo Nagai, Yasunobu Hirata
    Hypertension research : official journal of the Japanese Society of Hypertension 25(5) 773-8 2002年9月  査読有り
    In an attempt to find a strategy to modulate the proliferation of vascular endothelial cells, we examined whether constitutive activation of proto-oncogen protein p21 (Ras) induced the reentry of confluent human umbilical vascular endothelial cells (HUVECs) into the S phase. When an adenovirus construct expressing a constitutively active Ras mutant (Ad/RasG12V) was infected into HUVECs, their morphology changed strikingly and they appeared to be transformed. However, Ad/RasG12V-infected HUVECs did not enter the S phase, as determined by assessing 3H-thymidine incorporation. In accordance with the above results, the expression of cyclin A both at the transcript and protein levels did not increase in Ad/RasG12V-infected HUVECs relative to that in control cells, although the expression of cyclin D1 was induced in Ad/RasG12V-infected cells. Interestingly, the expression of the cyclin-dependent kinase (CDK) inhibitor p21cip1 was remarkably increased while that of p27kip1 did not decrease in Ad/RasG12V-infected HUVECs. Furthermore, CDK2 activity was not induced in Ad/RasG12V-infected HUVECs. These results suggested that the constitutive activation of Ras promoted the reentry of confluent HUVECs in the G0 phase into the G1 phase, but not into the S phase. The results also indicated that the constitutive activation of Ras might have induced the persistent expression of p21cip1 and p27kip1, and that this induction of p21cip1 and p27kip1 expression possibly caused the cell cycle arrest at the G1 phase.
  • 今井 靖, 林 同文, 川浪 大治, 都島 健介, 西村 剛, 山崎 憲, 野尻 剛史, 原田 智浩, 門前 幸志郎, 山崎 力, 永井 良三
    Journal of Cardiology 40(Suppl.1) 254-254 2002年8月  
  • Masataka Sata, Akihiro Takahashi, Kimie Tanaka, Miwa Washida, Nobukazu Ishizaka, Junya Ako, Masao Yoshizumi, Yasuyoshi Ouchi, Takahiro Taniguchi, Yasunobu Hirata, Mitsuhiro Yokoyama, Ryozo Nagai, Kenneth Walsh
    Arteriosclerosis, thrombosis, and vascular biology 22(8) 1305-9 2002年8月1日  査読有り
    OBJECTIVE: N-(3'4'-dimethoxycinnamoyl)-anthranilic acid (tranilast) is a drug that has been shown to reduce the incidence of restenosis after angioplasty in middle-scale clinical trials. Despite clinical interest in this drug, the pharmacological actions of tranilast remain relatively unexplored at a molecular level. METHODS AND RESULTS: We evaluated the effects of tranilast on vascular smooth muscle cell (VSMC) proliferation in wild-type mice and in mice lacking a cyclin-dependent kinase inhibitor, p21(WAF1) (p21). Tranilast potently inhibited the proliferation of VSMC cultures derived from wild-type mice, but VSMCs derived from p21-deficient (p21-/-) mice were unaffected by this treatment. In a mouse femoral artery model of vascular injury, tranilast administration to wild-type mice led to an upregulation of p21 expression and a decrease in the number of proliferating VSMCs, as determined by immunostaining for proliferating cell nuclear antigen. In contrast, tranilast had no effect on the number of proliferating cell nuclear antigen-positive cells in the injured arteries of p21-/- mice. Administration of tranilast significantly reduced the neointimal VSMC hyperplasia in wild-type mice at 4 weeks but had no effect on lesion formation in p21-/- mice. CONCLUSIONS: Our findings provide genetic evidence that tranilast inhibits intimal hyperplasia via a p21-dependent pathway, an activity that may contribute to its efficacy in the prophylactic treatment of postangioplasty restenosis.
  • H Okazaki, JI Osuga, K Tsukamoto, N Isoo, T Kitamine, Y Tamura, S Tomita, M Sekiya, N Yahagi, Y Iizuka, K Ohashi, K Harada, T Gotoda, H Shimano, S Kimura, R Nagai, N Yamada, S Ishibashi
    JOURNAL OF BIOLOGICAL CHEMISTRY 277(35) 31893-31899 2002年8月  
    Cholesterol ester (CE)-laden foam cells are a hallmark of atherosclerosis. To determine whether stimulation of the hydrolysis of cytosolic CE can be used as a novel therapeutic modality of atherosclerosis, we overexpressed hormone-sensitive lipase (HSL) in THP-1 macrophage-like cells by adenovirus-mediated gene delivery, and we examined its effects on the cellular cholesterol trafficking. We show here that the overexpression of HSL robustly increased neutral CE hydrolase activity and completely eliminated CE in the cells that had been preloaded with CE by incubation with acetylated low density lipoprotein. In these cells, cholesterol efflux was stimulated in the absence or presence of high density lipoproteins, which might be at least partially explained by the increase in the expression of ABCA1 Importantly, these effects were achieved without the addition of acyl-CoA:cholesterol acyltransferase inhibitor, cAMP, or even high density lipoproteins. Furthermore, the uptake and degradation of acetylated low density lipoprotein was significantly reduced probably by decreased expression of scavenger receptor A and CD36. Notably, the cells with stimulated CE hydrolysis did not exhibit either buildup of free cholesterol or cytotoxicity. In conclusion, increased hydrolysis of CE by the overexpression of HSL leads to complete elimination of CE from THP-1 foam cells not only by increasing efflux but also by decreasing influx of cholesterol.
  • K Monzen, R Nagai, Komuro, I
    TRENDS IN CARDIOVASCULAR MEDICINE 12(6) 263-269 2002年8月  
    Elucidating molecular mechanisms that regulate induction of cardiomyocyte differentiation is important because it may lead to practical therapeutic application for tissue regeneration in various heart diseases. Recent studies have demonstrated that some growth factors regulate expression of cardiac transcription factors and play a pivotal role in cardiac development. This study investigated the roles of bone morphogenetic proteins (BMPs) and their downstream molecules, using P19CL6 cardiomyogenic cell lines. Several lines of evidence show that BMPs are indispensable for cardiomyocyte differentiation and induce differentiation through two cardiac transcription factors, Csx/Nkx2-5 and GATA-4. Furthermore, it was demonstrated that not only Smads and TAK1, important mediators of transforming growth factor-beta signaling, but also their common target, ATF-2 transcription factor, play a critical role in cardiomyocyte differentiation. (C) 2002, Elsevier Science Inc.
  • M Sata, R Nagai
    CIRCULATION RESEARCH 91(4) 273-275 2002年8月  
  • Yasushi Imai, Takayuki Shindo, Koji Maemura, Masataka Sata, Yuichiro Saito, Yukiko Kurihara, Masahiro Akishita, Junichi Osuga, Shun Ishibashi, Kazuyuki Tobe, Hiroyuki Morita, Yoshio Oh-hashi, Toru Suzuki, Hiromitsu Maekawa, Kenji Kangawa, Naoto Minamino, Yoshio Yazaki, Ryozo Nagai, Hiroki Kurihara
    Arteriosclerosis, thrombosis, and vascular biology 22(8) 1310-5 2002年8月1日  査読有り
    OBJECTIVE: Several in vitro studies have implicated that adrenomedullin (AM) plays an important role in the pathogenesis of vascular injury and fatty streak formation. To test this possibility in vivo, we evaluated 2 experimental models using transgenic mice overexpressing AM in a vessel-selective manner (AMTg mice). METHODS AND RESULTS: Placement of a periarterial cuff on femoral arteries resulted in neointimal formation at 2 to 4 weeks to a lesser extent in AMTg mice than in their wild-type littermates (at 28 days, intima/media area ratio 0.45+/-0.14 versus 1.31+/-0.41, respectively; P<0.001). This vasculoprotective effect observed in AMTg mice was inhibited by N(omega)-nitro-L-arginine methyl ester. We further examined the effect of AM on hypercholesterolemia-induced fatty streak formation by crossing AMTg mice with apolipoprotein E knockout mice (ApoEKO mice). The extent of the formation of fatty streak lesions was significantly less in ApoEKO/AMTg mice than in ApoEKO mice (percent lesion area 12.0+/-3.9% versus 15.8+/-2.8%, respectively; P<0.05). Moreover, endothelium-dependent vasodilatation as indicative of NO production was superior in AMTg/ApoEKO mice compared with ApoEKO mice. CONCLUSIONS: Taken together, our data demonstrated that AM possesses a vasculoprotective effect in vivo, which is at least partially mediated by NO.
  • Naoto Kubota, Yasuo Terauchi, Toshimasa Yamauchi, Tetsuya Kubota, Masao Moroi, Junji Matsui, Kazuhiro Eto, Tokuyuki Yamashita, Junji Kamon, Hidemi Satoh, Wataru Yano, Philippe Froguel, Ryozo Nagai, Satoshi Kimura, Takashi Kadowaki, Tetsuo Noda
    The Journal of biological chemistry 277(29) 25863-6 2002年7月19日  査読有り
    The adipocyte-derived hormone adiponectin has been proposed to play important roles in the regulation of energy homeostasis and insulin sensitivity, and it has been reported to exhibit putative antiatherogenic properties in vitro. In this study we generated adiponectin-deficient mice to directly investigate whether adiponectin has a physiological protective role against diabetes and atherosclerosis in vivo. Heterozygous adiponectin-deficient (adipo(+/-)) mice showed mild insulin resistance, while homozygous adiponectin-deficient (adipo(-/-)) mice showed moderate insulin resistance with glucose intolerance despite body weight gain similar to that of wild-type mice. Moreover, adipo(-/-) mice showed 2-fold more neointimal formation in response to external vascular cuff injury than wild-type mice (p = 0.01). This study provides the first direct evidence that adiponectin plays a protective role against insulin resistance and atherosclerosis in vivo.
  • Satoru Muto, Atsu Aiba, Yuichirou Saito, Kazuki Nakao, Kenji Nakamura, Kyoichi Tomita, Tadaichi Kitamura, Masahiko Kurabayashi, Ryozo Nagai, Eiji Higashihara, Peter C Harris, Motoya Katsuki, Shigeo Horie
    Human molecular genetics 11(15) 1731-42 2002年7月15日  査読有り
    Mutations of either PKD1 or PKD2 are associated with autosomal dominant polycystic kidney disease (ADPKD). The molecular function of the gene product of PKD1, polycystin-1, in vitro has been elucidated recently, but the molecular pathological consequences of the loss of polycystin-1 in vivo have remained unclear. We have generated a mouse with a targeted deletion of exons 2-6 of Pkd1 to study the molecular defects in Pkd1 mutants. Homozygote embryos (Pkd1(-/-)) developed hydrops, cardiac conotruncal defects and renal cystogenesis. Total protein levels of beta-catenin in heart and kidney and c-MYC in heart were decreased in Pkd1(-/-) embryos. In the kidneys of Pkd1(-/-), the expression of E-cadherin and PECAM in basolateral membranes of renal tubules was attenuated, and tyrosine phosphorylation of epidermal growth factor receptor and Gab1 were constitutively enhanced when cystogenesis started on embryonic day (E) 15.5-16.5. Maternally administered pioglitazone, a thiazolidinedione compound, resolved these molecular defects of Pkd1(-/-). Treatment with pioglitazone improved survival of Pkd1(-/-) embryos and ameliorated the cardiac defects and the degree of renal cystogenesis. Long-term treatment with pioglitazone improved the endothelial function of adult Pkd1(+/-). These data indicated that molecular defects observed in Pkd1(-/-) embryos contributed to the pathogenesis of ADPKD and that thiazolidinediones had a compensatory effect on the pathway affected by the loss of polycystin-1. Pathways activated by thiazolidinediones may provide new therapeutic targets in ADPKD.
  • Toru Suzuki, Hiroaki Kohno, Akira Hasegawa, Shunichi Toshima, Toshihiro Amaki, Masahiko Kurabayashi, Ryozo Nagai, Toru Suzuki, Toshihiro Amaki, Ryozo Nagai, Akira Hasegawa, Shunichi Toshima, Masa-hiko Kurabayashi, Kazuyuki Shimada, Haruo Nakamura, Tamio Teramoto, Hiroshi Yamaguchi, Shin-ichiro Nishiyama, Hakuo Takahashi, Ichiro Michishita, Zinpei Sugano, Keiko Konoshi
    Clinical biochemistry 35(5) 347-53 2002年7月  査読有り
    OBJECTIVES: To examine the diagnostic performance of circulating oxidized low density lipoprotein levels as a biochemical risk marker of coronary heart disease. DESIGN AND METHODS: 361 patients with coronary artery disease and 710 healthy volunteers as normal controls were examined. Receiver-operating characteristics curve analysis in addition to statistical analysis (univariate, multivariate) were done to determine the usefulness of the assay. RESULTS: Patients with coronary artery disease showed significantly elevated circulating oxidized low density lipoprotein levels. Males less than 70 years of age showed a significant association between oxidized low density lipoprotein levels and coronary artery disease. Receiver-operating characteristics curve analysis showed superior performance (e.g., sensitivity, specificity) of oxidized low density lipoprotein as a diagnostic marker of coronary artery disease as compared against other lipid markers (total cholesterol, triglyceride, high density lipoprotein, lipoprotein (a), and total cholesterol to high density lipoprotein ratio) with optimal performance in younger males. CONCLUSIONS: Oxidized low density lipoprotein levels may be a promising biochemical risk marker of atherosclerotic disease, especially in young males.
  • K Inoue, K Matsuda, M Itoh, H Kawaguchi, H Tomoike, T Aoyagi, R Nagai, M Hori, Y Nakamura, T Tanaka
    HUMAN MOLECULAR GENETICS 11(15) 1775-1784 2002年7月  
    We isolated a mammalian gene whose expression transiently increased in response to intimal denudation of rabbit aorta. It was identical to a gene encoding a zinc transporter, ZNT5, reported very recently by others. Mice deficient for this gene showed poor growth and a decrease in bone density due to impairment of osteoblast maturation to osteocyte. More than 60% of male null mice died suddenly because of the bradyarrhythmias. Analysis of gene-expression profiles in murine hearts by means of an oligonucleotide microarray disclosed that a subset of genes encoding immediate-early response factors (IEGs) and heat shock proteins (HSPs) were down-regulated in Znt5-null mice. These results indicate that Znt5 protein plays an important role in maturation of osteoblasts and in maintenance of the cells involved in the cardiac conduction system, partly owing to dysregulated expression of IEGs and HSPs.
  • K Maemura, R Nagai
    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 34(7) 703-707 2002年7月  
  • H Toko, WD Zhu, E Takimoto, Shiojima, I, Y Hiroi, YZ Zou, T Oka, H Akazawa, M Mizukami, M Sakamoto, F Terasaki, Y Kitaura, H Takano, T Nagai, R Nagai, Komuro, I
    JOURNAL OF BIOLOGICAL CHEMISTRY 277(27) 24735-24743 2002年7月  
    Csx/Nkx2-5, which is essential for cardiac development of the embryo, is abundantly expressed in the adult heart. We here examined the role of Csx/Nkx2-5 in the adult heart using two kinds of transgenic mice. Transgenic mice that overexpress a dominant negative mutant of Csx/Nkx2-5 (DN-TG mice) showed degeneration of cardiac myocytes and impairment of cardiac function. Doxorubicin induced more marked cardiac dysfunction in DN-TG mice and less in transgenic mice that overexpress wild type Csx/Nkx2-5 (WT-TG mice) compared with non-transgenic mice. Doxorubicin induced cardiomyocyte apoptosis, and the number of apoptotic cardiomyocytes was high in the order of DN-TG mice, non-transgenic mice, and WT-TG mice. Overexpression of the dominant negative mutant of Csx/Nkx2-5 induced apoptosis in cultured cardiomyocytes, while expression of wild type Csx/Nkx2-5 protected cardiomyocytes from doxorubicin-induced apoptotic death. These results suggest that Csx/Nkx2-5 plays a critical role in maintaining highly differentiated cardiac phenotype and in protecting the heart from stresses including doxorubicin.
  • Masataka Sata, Yasunobu Hirata, Ryozo Nagai
    Hypertension research : official journal of the Japanese Society of Hypertension 25(4) 577-82 2002年7月  査読有り
    Fas ligand (FasL) is a death factor that induces apoptosis in cells bearing its receptor, Fas. Accumulating evidence indicates that the Fas/FasL system is involved not only in apoptosis but also in cell-activation signals. Recently, it was reported that local stimulation of Fas in vivo using an agonistic antibody triggers inflammatory cell infiltration and neoangiogenesis independently of apoptosis. On the other hand, Fas/FasL interaction has been proposed to control the growth and development of new subretinal vessels. Here, we evaluated the potential involvement of Fas/FasL interaction in collateral development in response to tissue ischemia. Hindlimb ischemia was induced in C57BL/6J (wild-type), B6-gld(FasL -/-), and B6-lpr(Fas -/-) mice by resection of the right femoral artery. The blood flow recovery of FasL -/- or Fas -/- mice was similar to that of wild-type mice, as determined using a laser Doppler imaging system. There was no significant difference in capillary density of the ischemic calf muscle among the mice, as determined by anti-CD31 immunostaining. We did not find any difference in the number of infiltrating inflammatory cells or in vascular endothelial growth factor expression. These results indicate that postnatal angiogenesis in response to acute ischemia can occur independently of the endogenous Fas/FasL interaction.
  • M Yamasaki, J Kawai, T Nakaoka, T Ogita, R Nagai, T Fujita
    JOURNAL OF HYPERTENSION 20 S178-S178 2002年6月  
  • H Nishimatsu, E Suzuki, H Satonaka, D Nagata, H Hayakawa, A Goto, T Kitamura, R Nagai, T Fujita, Y Hirata
    JOURNAL OF HYPERTENSION 20 S276-S276 2002年6月  
  • Y Saito, T Nakamura, H Sumino, M Kurabayashi, R Nagai
    JOURNAL OF HYPERTENSION 20 S103-S103 2002年6月  
  • E Suzuki, H Nishimatsu, H Satonaka, A Goto, M Omata, T Fujita, R Nagai, Y Hirata
    JOURNAL OF HYPERTENSION 20 S97-S97 2002年6月  
  • T Uchiyama, T Nakamura, T Utsugi, Y Saito, Y Ohyama, M Negishi, A Tanaka, S Tomono, S Kawazu, R Nagai, M Kurabayashi
    DIABETES 51 A511-A511 2002年6月  
  • Kou-ichi Tomaru Ki, Masashi Arai, Tomoyuki Yokoyama, Yasushi Aihara, Ken-ichi Sekiguchi Ki, Toru Tanaka, Ryozo Nagai, Masahiko Kurabayashi
    Journal of molecular and cellular cardiology 34(6) 649-59 2002年6月  査読有り
    Lipopolysaccharide (LPS) has a profound effect on cardiac performance through a collapse of the vasculature. In this study, we determined whether LPS has a direct effect on the cardiac myocytes by examining the expression of the BNP gene in cultured neonatal rat cardiac myocytes. Northern blot analysis showed that LPS induces the expression of the BNP gene. Time-course experiments revealed that BNP mRNA levels were increased 1 h after LPS stimulation. Enhanced induction of BNP was observed 3 h after stimulation when expression of CD14, a specific receptor for LPS, was markedly induced. LPS-mediated BNP expression was completely inhibited by the pretreatment of SB203580, a specific inhibitor for p38 MAPK as well as by genistein, a broad range tyrosine kinase inhibitor. In accordance with these results, LPS increases phosphorylation of p38 mitogen-activated protein kinase (MAPK). Transient transfection assays revealed that low dose (1 ng/ml) of LPS induces the luciferase activity derived from the construct containing the BNP promoter spanning from -1000 and +80 in front of the luciferase gene. Cotransfection of the expression vectors for constitutive active forms of Rac1, MKK3 and p38 MAPK significantly increased BNP promoter activity. Mutation of the GATA sequence located at -95 and -84 abolished such an induction of BNP promoter activity. Overexpression of CD14 enhanced the LPS's effect on BNP promoter. These results indicate that LPS induces the BNP gene expression through a pathway involving CD14, Rac1, p38 MAPK and GATA elements. In addition to the induction of BNP expression by hemodynamic overload, our data suggest that elevated levels of BNP under the endotoxemic condition is partly mediated through the increased expression of CD14, which lies upstream of the Rac1-p38 MAPK pathway.
  • Y Ikeda, Y Hiroi, T Hosoda, T Utsunomiya, S Matsuo, T Ito, J Inoue, T Sumiyoshi, H Takano, R Nagai, Komuro, I
    CIRCULATION JOURNAL 66(6) 561-563 2002年6月  
    The homeobox transcription factor CSX/NKX2.5, which is a vertebrate homologue of the Drosophila gene tinman, is essential for cardiac development. It is expressed in the early cardiac mesoderm and in heart muscle lineage throughout life. Homozygous deletion of CSX/NKX2.5 causes early embryonic lethality in mice because cardiac development is arrested at the linear heart tube stage. Heterozygous mutation of human CSX/NKX2.5 has been associated with various congenital heart diseases such as atrial septal defect (ASD), ventricular septal defect, tetralogy of Fallot, and tricuspid valve abnormalities, including Ebstein's anomaly. Additionally, CSX/NKX2.5 mutation causes atrioventricular (AV) conduction block with or without associated congenital heart diseases. Ten different heterozygous mutations have been already reported and a new point mutation, which is a C-to-A transition (Cys264ter) at nucleotide 901 of CSX/NKX2.5, results in the production of a truncated protein occurring COOH-terminal to the homeodomain of CSX/NKX2.5. The mutation was found in a patient with familial ASD and first-degree AV block; 4 members from 3 generations had secundum-type ASD and first-degree AV block.
  • Ryuichi Aikawa, Yuko Nitta-Komatsubara, Sumiyo Kudoh, Hiroyuki Takano, Toshio Nagai, Yoshio Yazaki, Ryozo Nagai, Issei Komuro
    Cytokine 18(4) 179-83 2002年5月21日  査読有り
    Many studies have indicated that oxidative stress induces apoptosis in cardiomyocytes, but its mechanism remains unknown. We examined whether tumor necrosis factor-alpha (TNF-alpha) is involved in oxidative stress-induced cardiomyocyte apoptosis. Pretreatment with anti-TNF-alpha antibody significantly decreased the number of H(2)O(2)-induced TUNEL-positive cardiomyocytes. Expression of TNF-alpha gene was upregulated by H(2)O(2), and H(2)O(2) mildly but significantly increased the concentration of TNF-alpha in the culture medium. Although neither low dose of H(2)O(2) nor TNF-alpha induced apoptosis, stimulation with H(2)O(2) and TNF-alpha synergistically increased apoptosis. These results suggest that oxidative stress induces apoptosis of cardiac myocytes partly through TNF-alpha.
  • Etsu Suzuki, Hiroaki Nishimatsu, Hiroshi Satonaka, Kenneth Walsh, Atsuo Goto, Masao Omata, Toshiro Fujita, Ryozo Nagai, Yasunobu Hirata
    Circulation research 90(9) 1004-11 2002年5月17日  査読有り
    It is well known that angiotensin II (Ang II) is implicated in the phenotypic modulation and hypertrophy of vascular smooth muscle cells (VSMCs). To study the mechanisms by which Ang II contributes to the pathological changes of VSMCs, we examined whether Ang II stimulated myocyte enhancer factor 2 (MEF2)- and calcineurin/nuclear factor of activated T cell (NFAT)-dependent transcriptional activation of genes in VSMCs. Ang II increased the DNA binding activity of MEF2A and its expression at the protein level. Ang II induced c-jun promoter activity, and this increase was inhibited by dominant-negative mutants of MEF2A and mitogen-activated protein kinase kinase 6 but not by calcineurin inhibitors. Ang II stimulated NFAT DNA binding activity and NFAT-dependent gene transcription, and these effects of Ang II were inhibited by calcineurin inhibitors. Furthermore, Ang II induced the promoter activity of the nonmuscle-type myosin heavy chain B gene, which we used as a marker of the dedifferentiated state of VSMCs, and this increase was inhibited by calcineurin inhibitors but not by the dominant-negative mutants of MEF2A or mitogen-activated protein kinase kinase 6. Finally, Ang II increased protein synthesis, and this increase was inhibited by infection with an adenovirus construct that expresses the dominant-negative mutant of MEF2A but not by calcineurin inhibitors. These results suggest that Ang II stimulates the MEF2- and calcineurin/NFAT-dependent pathways and that these pathways have distinct roles in VSMCs.
  • Yokoyama, I, Y Inoue, K Yonekura, M Tateno, R Nagai, T Momose, K Ohtomo
    JOURNAL OF NUCLEAR MEDICINE 43(5) 181P-181P 2002年5月  
  • Y Seko, S Ishiyama, T Nishikawa, T Kasajima, M Hiroe, S Suzuki, S Ishiwata, S Kawai, Y Tanaka, M Azuma, T Kobata, H Yagita, K Okumura, R Nagai
    CARDIOVASCULAR PATHOLOGY 11(3) 166-170 2002年5月  
    Background: T-cell-mediated myocardial damage is known to be involved in acute myocarditis and dilated cardiomyopathy. Recently, we found that tumor necrosis factor (TNF) ligand superfamily costimulatory molecules, especially 4-1BBL, played an important role in the myocardial damage of murine acute viral myocarditis. Methods and results: To investigate the roles for CD27L, CD30L, OX40L and 4-1BBL, which belong to TNF ligand superfamily, in the development of acute myocarditis and dilated cardiomyopathy, we analyzed the expression of these antigens in the myocardial tissues of patients with acute myocarditis and dilated cardiomyopathy. We also examined expression of the receptors for these molecules, CD27, CD30, OX40 and 4-1BB, which belong to TNF receptor superfamily, on the infiltrating cells. Strong expression of CD27L, CD30L and 4-1BBL and weak to moderate expression of OX40L was found in the cardiac myocytes of patients with acute myocarditis. Moderate expression of CD27L, CD30L and 4-1BBL and weak expression of OX40L was found on the cardiac myocytes of patients with dilated cardiomyopathy. Most of the infiltrating cells expressed CD27, CD30 and 4-1BB and a part of the infiltrating cells expressed OX40. Conclusions: Our Findings suggest that expression of TNF ligand superfamily costimulatory molecules on cardiac myocytes may play a role in the cell-mediated myocardial damage in patients with acute myocarditis and dilated cardiomyopathy as in murine viral myocarditis. (C) 2002 Elsevier Science Inc. All rights reserved.
  • N Yahagi, H Shimano, AH Hasty, T Matsuzaka, T Ide, T Yoshikawa, M Amemiya-Kudo, S Tomita, H Okazaki, Y Tamura, Y Iizuka, K Ohashi, J Osuga, K Harada, T Gotoda, R Nagai, S Ishibashi, N Yamada
    JOURNAL OF BIOLOGICAL CHEMISTRY 277(22) 19353-19357 2002年5月  
    Obesity is a common nutritional problem often associated with diabetes, insulin resistance, and fatty liver (excess fat deposition in liver). Leptin-deficient Lep(ob)/Lep(ob) mice develop obesity and those obesity-related syndromes. Increased lipogenesis in both liver and adipose tissue of these mice has been suggested. We have previously shown that the transcription factor sterol regulatory element-binding protein-1 (SREBP-1) plays a crucial role in the regulation of lipogenesis in vivo. To explore the possible involvement of SREBP-1 in the pathogenesis of obesity and its related syndromes, we generated mice deficient in both leptin and SREBP-1. In doubly mutant Lep(ob/ob) x Srebp-1(-/-) mice, fatty livers were markedly attenuated, but obesity and insulin resistance remained persistent. The mRNA levels of lipogenic enzymes such as fatty acid synthase were proportional to triglyceride accumulation in liver. In contrast, the mRNA abundance of SREBP-1 and lipogenic enzymes in the adipose tissue of Lep(ob)/Lep(ob) mice was profoundly decreased despite sustained fat, which could explain why the SREBP-1 disruption had little effect on obesity. In conclusion, SREBP-1 regulation of lipogenesis is highly involved in the development of fatty livers but does not seem to be a determinant of obesity in Lep(ob)/Lep(ob) mice.
  • Keiko Fukino, Toru Suzuki, Yuichiro Saito, Takayuki Shindo, Toshihiro Amaki, Masahiko Kurabayashi, Ryozo Nagai
    Biochemical and biophysical research communications 293(1) 332-7 2002年4月26日  査読有り
    Advanced age is a major risk factor of peripheral artery disease. We examined the effects of the aging-suppressor gene klotho on angiogenesis in response to ischemia by introducing ischemic hindlimb model in mice heterozygously deficient for the klotho gene and in wild type mice. Blood flow recovery as assessed by laser doppler perfusion imaging and angiogenesis as assessed by density of PECAM-1/CD31-positive positive capillaries were markedly impaired in mice heterozygously deficient for the klotho gene (both <0.05). Our findings show that the aging-suppressor gene klotho affects angiogenesis and the possibility that age-related impairment of angiogenesis might be regulated by the klotho gene. Our results present a new possibility of therapeutic angiogenesis for patients of advanced age.
  • 住友 秀次, 齋藤 幹, 杉浦 清了, 笠岡 祐二, 速水 紀幸, 小早川 直, 村川 裕二, 大野 実, 平田 恭信, 永井 良三
    Circulation journal : official journal of the Japanese Circulation Society 66 911-911 2002年4月20日  

書籍等出版物

 21
もっとみる

所属学協会

 5

共同研究・競争的資金等の研究課題

 91
もっとみる
一覧へ戻る