研究者業績

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

受賞

 7

論文

 965
  • 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  

MISC

 1923
  • 前村 浩二, 永井 良三
    動脈硬化 29(Suppl.) 218-218 2001年5月  
  • 相澤 健一, 鈴木 亨, 倉林 正彦, 天木 幹博, 宮本 索, 今井 靖, 前村 浩二, 水野 由子, 永井 良三
    動脈硬化 29(Suppl.) 215-215 2001年5月  
  • Yokoyama, I, K Yonekura, Y Inoue, R Nagai, K Ohtomo, T Momose, T Moritan, M Tateno
    JOURNAL OF NUCLEAR MEDICINE 42(5) 181P-181P 2001年5月  
  • A Saiura, M Sata, Y Hirata, R Nagai, M Makuuchi
    NATURE MEDICINE 7(5) 636-636 2001年5月  
  • 鈴木 将敏, 石坂 信和, 塚本 和久, 南 佳余, 黄 文懋, 相澤 達, 森 一郎, 大野 実, 永井 良三
    動脈硬化 29(Suppl.) 225-225 2001年5月  
  • 相澤 健一, 鈴木 亨, 倉林 正彦, 天木 幹博, 宮本 索, 今井 靖, 前村 浩二, 水野 由子, 永井 良三
    動脈硬化 29(Suppl.) 215-215 2001年5月  
  • 今井 靖, 栗原 裕基, 新藤 隆行, 前村 浩二, 佐田 政隆, 斉藤 勇一郎, 秋下 雅弘, 大須賀 淳一, 矢崎 義雄, 永井 良三
    動脈硬化 29(Suppl.) 211-211 2001年5月  
  • K Chisaki, T Nakajima, K Iwasawa, H Iida, A Matsumoto, M Tada, Y Komatsu, K Hirose, K Miyamoto, Y Okuda, Y Shiratori, A Goto, Y Hirata, R Nagai, M Omata
    Japanese heart journal 42(3) 339-53 2001年5月  査読有り
    The purpose of this study was to clarify whether physiological concentrations of bile acids could affect endothelial nitric oxide production. We investigated the relationships between clinical concentrations of individual bile acids observed in patients with hepatobiliary diseases and endothelial nitric oxide production induced by each bile acid. Fifteen serum bile acids were measured using high-performance liquid chromatography combined with enzymatic fluorometry in 8 patients with liver cirrhosis, obstructive jaundice, and 8 healthy subjects. The effects of individual bile acids on nitric oxide production were examined in human umbilical endothelial cells by measuring the concentration of NO2- in the cultured medium. NO release in the blood was also determined by measuring the NO2-/NO3- concentration in these patients. In patients with hepatobiliary diseases, the plasma concentrations of chenodeoxycholic acid, ursodeoxycholic acid and cholic acid (free acid, taurine and glycine conjugates) were markedly elevated. Incubation of cells with chenodeoxycholic acid and deoxycholic acid (free acid, taurine and glycine conjugates) enhanced NO2- production in a concentration-dependent manner, while cholic acid (free and its conjugates) did not. The effects of individual bile acids on nitric oxide production were additive. Patients with liver cirrhosis and obstructive jaundice had higher plasma levels of NO2-/NO3- levels than the control subjects. These results suggest that increased plasma concentrations of chenodeoxycholic acid (free, taurine and glycine conjugates) in patients with hepatobiliary diseases may induce endothelial nitric oxide production. Thus, nitric oxide production induced by bile acids may be involved in the pathogenesis of circulatory abnormalities in patients with liver diseases.
  • S Sakurai, K Takenaka, Shiojima, I, F Watanabe, M Sonoda, K Uno, Y Kuwada, K Nakahara, R Nagai
    ECHOCARDIOGRAPHY-A JOURNAL OF CARDIOVASCULAR ULTRASOUND AND ALLIED TECHNIQUES 18(4) 303-304 2001年5月  
  • Y Wada, J Suzuki, M Kawauchi, M Kurabayashi, K Tsukioka, T Zhang, M Endoh, K Takayama, R Nagai, S Takamoto, M Isobe, J Amano
    The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 20(5) 590-4 2001年5月  査読有り
    Early growth-response factor 1 (Egr-1) and basic transcriptional element-binding protein 2 (BTEB2) are transcriptional factors that regulate multiple genes involved in phenotypic changes of smooth muscle cells (SMCs), one of the outstanding pathologic features of chronic cardiac allograft rejection. In this study, we used a heterotopic abdominal heart transplant model in monkeys to evaluate the roles of these molecules in graft coronary vasculopathy. We demonstrated that Egr-1 and BTEB2 are induced in vascular SMCs of rejected cardiac allografts well before morphologic changes, such as intimal thickening. These findings suggest that expression of Egr-1 and BTEB2 is one of the initial events in allograft angiopathy.
  • 遠藤 陽子, 原田 智浩, 青柳 昭彦, 宇野 漢成, 竹中 克, 野尻 剛史, 高橋 利之, 山崎 憲, 石坂 信和, 鈴木 順一, 杉浦 清了, 大野 実, 小室 一成, 平田 恭信, 永井 良三, 沢田 哲治
    Japanese circulation journal 65 613-613 2001年4月20日  
  • 鈴木 将敏, 平田 恭信, 中村 文隆, 高橋 利之, 大野 実, 小室 一成, 永井 良三, 出月 健夫, 朝日奈 昭彦
    Japanese circulation journal 65 2001年4月20日  
  • 笠岡 祐二, 伊藤 敦彦, 羽田 勝征, 高橋 尚彦, 犀川 哲典, 岸田 信也, 福井 栄一, 速水 紀幸, 安喰 恒輔, 山下 武志, 村川 裕二, 永井 良三, 小俣 政男
    Therapeutic Research 22(4) 805-805 2001年4月  
    発作性心房細動の薬物治療において,Ic群薬が心房粗動を惹起しやすいという観察は得られなかった
  • A Saiura, M Sata, Y Hirata, R Nagai, M Makuuchi
    NATURE MEDICINE 7(4) 382-383 2001年4月  
  • R Tozawa, S Ishibashi, J Osuga, K Yamamoto, H Yagyu, K Ohashi, Y Tamura, N Yahagi, Y Iizuka, H Okazaki, K Harada, T Gotoda, H Shimano, S Kimura, R Nagai, N Yamada
    JOURNAL OF BIOLOGICAL CHEMISTRY 276(16) 12624-12628 2001年4月  
    The asialoglycoprotein receptor is an abundant hetero-oligomeric endocytic receptor that is predominantly expressed on the sinusoidal surface of the hepatocytes, A number of physiological and pathophysiological functions have been ascribed to this hepatic lectin (HL), the removal of desialylated serum glycoproteins and apoptotic cells, clearance of lipoproteins, and the sites of entry for hepatotropic viruses. The assembly of two homologous subunits, HL-1 and HL-2, is required to form functional, high affinity receptors on the cell surface. However, the importance of the individual subunits for receptor transport to the cell surface is controversial. We have previously generated HL-S-deficient mice and showed that the expression of HL-1 was significantly reduced, and the functional activity as the asialoglycoprotein receptor was virtually eliminated. However, we failed to detect phenotypic abnormalities. To explore the significance of the major HL-1 subunit for receptor expression and function in vivo, we have disrupted the HL-1 gene in mice. Homozygous HL-1-deficient animals are superficially normal. HL-2 expression in the liver is virtually abrogated, indicating that HL-1 is strictly required for the stable expression of HL-2, Although these mice are almost unable to clear asialo-orosomucoid, a high affinity ligand for asialoglycoprotein receptor, they do not accumulate desialylated glycoproteins or lipoproteins in the plasma.
  • H Miki, T Yamauchi, R Suzuki, K Komeda, A Tsuchida, N Kubota, Y Terauchi, J Kamon, Y Kaburagi, J Matsui, Y Akanuma, R Nagai, S Kimura, K Tobe, T Kadowaki
    Molecular and cellular biology 21(7) 2521-32 2001年4月  査読有り
    To investigate the role of insulin receptor substrate 1 (IRS-1) and IRS-2, the two ubiquitously expressed IRS proteins, in adipocyte differentiation, we established embryonic fibroblast cells with four different genotypes, i.e., wild-type, IRS-1 deficient (IRS-1(-/-)), IRS-2 deficient (IRS-2(-/-)), and IRS-1 IRS-2 double deficient (IRS-1(-/-) IRS-2(-/-)), from mouse embryos of the corresponding genotypes. The abilities of IRS-1(-/-) cells and IRS-2(-/-) cells to differentiate into adipocytes are approximately 60 and 15%, respectively, lower than that of wild-type cells, at day 8 after induction and, surprisingly, IRS-1(-/-) IRS-2(-/-) cells have no ability to differentiate into adipocytes. The expression of CCAAT/enhancer binding protein alpha (C/EBPalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma) is severely decreased in IRS-1(-/-) IRS-2(-/-) cells at both the mRNA and the protein level, and the mRNAs of lipoprotein lipase and adipocyte fatty acid binding protein are severely decreased in IRS-1(-/-) IRS-2(-/-) cells. Phosphatidylinositol 3-kinase (PI 3-kinase) activity that increases during adipocyte differentiation is almost completely abolished in IRS-1(-/-) IRS-2(-/-) cells. Treatment of wild-type cells with a PI 3-kinase inhibitor, LY294002, markedly decreases the expression of C/EBPalpha and PPARgamma, a result which is associated with a complete block of adipocyte differentiation. Moreover, histologic analysis of IRS-1(-/-) IRS-2(-/-) double-knockout mice 8 h after birth reveals severe reduction in white adipose tissue mass. Our results suggest that IRS-1 and IRS-2 play a crucial role in the upregulation of the C/EBPalpha and PPARgamma expression and adipocyte differentiation.
  • 山下 武志, 村川 裕二, 佐藤 美知子, 安喰 恒輔, 速水 紀幸, 福井 栄一, 笠岡 祐二, 守随 豊, 永井 良三
    心電図 = Electrocardiology 21 28-28 2001年3月25日  
  • T Takahashi, Y Sugishita, T Nojiri, T Shimizu, A Yao, K Kinugawa, K Harada, R Nagai
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 281(4) 1057-1062 2001年3月  
    Hypoxia-inducible factor 1 (HIF-1) is composed of HIF-1 alpha and arylhydocarbon nuclear receptor translocator (ARNT), which belong to the basic-helix-loop-helix-Per/ARNT/Sim bHLH-PAS) family of transcription factors. HLF plays key roles in oxygen homeostasis and embryonic cardiovascular development. In this study, we have cloned cDNAs encoding the chick HIF-1 alpha from cultured embryonic ventricular myocytes (CEVM) and then examined its expression in various embryonic tissues. The deduced amino acid sequence of the chick HIF-1 alpha cDNA showed 79% identity with that of the human HIF-1 alpha cDNA. In contrast, sequence homology between the chick HIF-1 alpha and endothelial PAS protein 1 (EPAS1), another member of the bHLH-PAS proteins, was only low (49%). HIF-1 alpha mRNA was expressed abundantly in CEVM., but scarcely in the liver, which was quite different from expression pattern of EPAS1 mRNA. These data suggest that HIF-1 alpha may be involved in embryonic cardiovascular development. HIF-1 alpha and EPAS1 may play distinct roles during developmental stages. (C) 2001 Academic Press.
  • Z Chen, S Ishibashi, S Perrey, J Osuga, T Gotoda, T Kitamine, Y Tamura, H Okazaki, N Yahagi, Y Iizuka, F Shionoiri, K Ohashi, K Harada, H Shimano, R Nagai, N Yamada
    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 21(3) 372-377 2001年3月  
    Atherosclerotic coronary heart disease is a common complication of the insulin resistance syndrome that can occur with or without diabetes mellitus, Thiazolidinediones (TZDs), which are insulin-sensitizing antidiabetic agents, can modulate the development of atherosclerosis not only by changing the systemic metabolic conditions associated with insulin resistance but also by exerting direct effects on vascular wall cells that express peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a nuclear receptor for TZDs. Here we show that troglitazone, a TZD, significantly inhibited fatty streak lesion formation in apolipoprotein E-knockout mice fed a high-fat diet (en face aortic surface lesion areas were 6.9+/-2.5% vs 12.7+/-4.7%, P&lt;0.05; cross-sectional lesion areas were 191 974+/-102 911 &lt;mu&gt;m(2) vs 351 738+/-175 597 mum(2), P&lt;0.05; n=10). Troglitazone attenuated hyperinsulinemic hyperglycemia and increased high density Lipoprotein cholesterol levels. In the aorta, troglitazone markedly increased the mRNA levels of CD36, a scavenger receptor for oxidized low density lipoprotein, presumably by upregulating its expression, at least in part, in the macrophage foam cells. These results indicate that troglitazone potently inhibits fatty streak lesion formation by modulating both metabolic extracellular environments and arterial wall cell functions.
  • K Aizawa, Y Kaneko, T Yamagishi, T Utsugi, T Suzuki, S Ishikawa, A Otaki, Y Morishita, A Hasegawa, M Kurabayashi, R Nagai
    PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY 24(3) 381-383 2001年3月  
    Screw-in atrial pacing leads are widely used. Cardiac tamponade is a complication. An 82-year-old woman with advanced atrioventricular block underwent permanent pacemaker implantation and subsequently developed cardiac tamponade. At surgery, the lead-tip screw was found penetrated through the right atrium but nor through the pericardium. The source of bleeding was confirmed to scratching the inner pericardial membrane by the screw tip. Although cardiac tamponade due to perforation and leakage is known, tamponade caused by the trauma of an atrial screw on the pericardium with resultant ooze is less well described.
  • K Aizawa, Y Kaneko, T Yamagishi, T Utsugi, T Suzuki, S Ishikawa, A Otaki, Y Morishita, A Hasegawa, M Kurabayashi, R Nagai
    Pacing and clinical electrophysiology : PACE 24(3) 381-3 2001年3月  査読有り
    Screw-in atrial pacing leads are widely used. Cardiac tamponade is a complication. An 81-year-old woman with advanced atrioventricular block underwent permanent pacemaker implantation and subsequently developed cardiac tamponade. At surgery, the lead-tip screw was found penetrated through the right atrium but not through the pericardium. The source of bleeding was confirmed to scratching the inner pericardial membrane by the screw tip. Although cardiac tamponade due to perforation and leakage is known, tamponade caused by the trauma of an atrial screw on the pericardium with resultant ooze is less well described.
  • T Suzuki, H Kohno, S Toshima, A Hasegawa, M Kurabayashi, R Nagai
    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 37(2) 248A-248A 2001年2月  
  • 林 同文, 深山 源太, 山崎 力, 藤田 英雄, 森田 啓行, 今井 靖, 吹野 恵子, 野尻 剛史, 山崎 憲, 永井 良三
    日本内科学会雑誌 90(臨増) 136-136 2001年2月  
  • 林 同文, 深山 源太, 山崎 力, 藤田 英雄, 森田 啓行, 今井 靖, 吹野 恵子, 野尻 剛史, 山崎 憲, 永井 良三
    日本内科学会雑誌 90(臨増) 134-134 2001年2月  
  • 吹野 恵子, 森田 啓行, 今井 靖, 野尻 剛史, 永井 良三, 林 同文, 深山 源太, 山崎 力, 藤田 英雄, 杉山 卓郎
    日本内科学会雑誌 90(臨増) 194-194 2001年2月  
  • 吹野 恵子, 鈴木 亨, 永井 良三, 山崎 力
    臨床高血圧 7(1) 50-51 2001年2月  
  • 吹野 恵子, 鈴木 亨, 永井 良三, 山崎 力
    臨床高血圧 7(1) 48-49 2001年2月  
  • 水野 由子, 鈴木 亨, 山崎 力, 永井 良三
    臨床高血圧 7(1) 54-55 2001年2月  
  • 相澤 健一, 鈴木 亨, 山崎 力, 永井 良三
    臨床高血圧 7(1) 52-53 2001年2月  
  • T Ogata, R Nagai, M Kurabayashi, Y Hoshino, K Sekiguchi, K Kowase, A Akuzawa, S Ishikawa, I Takeyoshi, Y Morishita
    The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 20(2) 228-228 2001年2月  査読有り
  • H Morita, H Kurihara, Y Imai, T Sugiyama, C Hamada, E Sakai, M Mori, R Nagai
    THROMBOSIS AND HAEMOSTASIS 85(2) 226-230 2001年2月  
    The platelet-collagen receptor, glycoprotein Ia/IIa (integrin alpha (2)beta (1)) plays a fundamental role in the adhesion of platelets to fibrillar collagen, an event leading to platelet activation and thrombus formation and contributing to the pathogenesis of thrombotic disease. Further, glyco protein Ia/IIa receptor density and function may be associated with two linked and silent polymorphisms (C-807/T and (873)G/A) within the glycoprotein Ia gene. We tested the extent to which these polymorphisms serve as genetic markers of myocardial infarction in a Japanese population. A case-control study was carried out using 210 Japanese myocardial infarction patients and 420 age- and sex-matched controls. Genotyping was accomplished using PCR followed by melting curve analysis with specific fluorescent hybridization probes. The (CC)-C-807. CT, TT genotypes linked perfectly to the (873)GG, GA, AA genotypes, respectively. Allele frequencies of the T-807 ((873)A) variant were similar in the control and patient groups (0.373 vs. 0.352). The T-807 and (873)A variants of platelet glycoprotein la gene are common and in a perfect linkage in the Japanese population, but it appears unlikely that the T-807 ((873)A) variant represents a useful marker of increased risk for myocardial infarction.
  • T Aizawa, N Ishizaka, K Kurokawa, R Nagai, H Nakajima, JI Taguchi, M Ohno
    KIDNEY INTERNATIONAL 59(2) 645-653 2001年2月  
    Background. We have recently found that chronic infusion of angiotensin II (Ang II) into rats resulted in an impairment of renal function, whereas norepinephrine (NE) infusion did not. We investigated whether chronic infusion of Ang II and NE caused different degrees of renal cell apoptosis and proliferation. Methods. Rats were made hypertensive via continuous infusion of either Ang II or NE for up to seven days. Renal cell apoptosis and proliferation were analyzed by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) technique and staining with antibody against proliferating cell nuclear antigen (PCNA), respectively. In some experiments, an inducer or inhibitor of heme oxygenase-l (HO-1) was administered to investigate the possible role of HO-1 in renal cell homeostasis. Results. Infusion of Ang II. but not NE, resulted in approximately a sevenfold increase in bax protein at seven days of infusion. The TUNEL assay revealed that Ang II infusion significantly increased the number of apoptotic cells, whereas NE infusion did not. TUNEL- and PCNA-positive cells were mainly seen in the tubulointerstitial region of Ang II-infused rats. Ang II induced increased positivity of TUNEL, and PCNA was blocked completely by losartan, but only partially by hydralazine. Induction of HO-1 reduced and inhibition of HO increased Ang II-induced cell proliferation. Conclusions. These data suggest that Ang II plays a pivotal role in the development of renal cell proliferation and apoptosis in the setting of hypertension. The renal HO system may modulate proliferative and pro-apoptotic effects of Ang II.
  • WQ Zhu, H Sano, R Nagai, K Fukuhara, A Miyazaki, S Horiuchi
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 280(4) 1183-1188 2001年2月  
    Galectin-3, a member of beta -galactoside-binding lectin family, is suggested to be an AGE-receptor. To examine this possibility, we prepared CHO cells overexpressing human galectin-3 (galectin-3-CHO cells). Galectin-3-CHO cells showed a specific and saturable binding to I-125-AGE-BSA with Kd of 3.1 mug/ml. I-125-AGE-BSA was endocytosed by galectin-3-CHO cells and underwent lysosomal degradation. The endocytosis of I-125-AGE-BSA was inhibited not only by unlabeled AGE-BSA but also by acetylated LDL and oxidized LDL, ligands for the scavenger receptor family. Furthermore, I-125-oxidized LDL and I-125-acetylated LDE were actively endocytosed by galectin-3-CHO cells and the incubation with acetyl-LDL led to intracellular accumulation of cholesteryl esters, indicating the role of galectin-3 in endocytosis of AGE-proteins and modified LDLs. Since galectin-3 was localized and upregulated in foam cells at human atherosclerotic lesions, the present results suggest that galectin-3 plays an important role in formation of atherosclerotic lesions in vivo, by modulating endocytic uptake of AGE-proteins and modified LDLs. (C) 2001 Academic Press.
  • A Nakajima, K Wada, H Miki, N Kubota, N Nakajima, Y Terauchi, S Ohnishi, L J Saubermann, T Kadowaki, R S Blumberg, R Nagai, N Matsuhashi
    Gastroenterology 120(2) 460-9 2001年2月  査読有り
    BACKGROUND & AIMS: Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor whose activation has been linked to several physiologic pathways including those related to the regulation of intestinal inflammation. We sought to determine whether PPAR gamma could function as an endogenous anti-inflammatory pathway in a murine model of intestinal ischemia-reperfusion (I/R) injury. METHODS: PPAR gamma-deficient and wild-type mice were examined for their response to I/R procedure. Treatment with a PPAR gamma-specific ligand was also performed. RESULTS: In a murine model of intestinal I/R injury, we observed more severe injury in PPAR gamma-deficient mice and protection against local and remote tissue injury in mice treated with a PPAR gamma-activating ligand, BRL-49653. Activation of PPAR gamma resulted in down-regulation of intercellular adhesion molecule 1 expression by intestinal endothelium and tissue tumor necrosis factor alpha messenger RNA levels most likely by inhibition of the NF-kappa B pathway. CONCLUSIONS: These data strongly suggest that an endogenous PPAR gamma pathway exists in tissues that may be amenable to therapeutic manipulation in I/R-related injuries.
  • K Sekiguchi, M Kurabayashi, Y Oyama, Y Aihara, T Tanaka, H Sakamoto, Y Hoshino, T Kanda, T Yokoyama, Y Shimomura, H Iijima, Y Ohyama, R Nagai
    Circulation research 88(1) 52-8 2001年1月19日  査読有り
    Recent studies have shown that the homeobox gene Hex plays an important role in inducing differentiation of vascular endothelial cells. In this study, we examined the expression of Hex in vascular smooth muscle cells (VSMCs) in vitro and in vivo. Immunohistochemistry showed a marked induction of Hex protein in neointimal VSMCs after balloon injury in rat aorta. Western and reverse transcriptase-polymerase chain reaction analyses demonstrated that Hex was abundantly expressed in cultured VSMCs, whereas it was undetectable in other cell types or in normal aorta. The expression pattern of Hex was similar to that of SMemb/NMHC-B, a nonmuscle isoform of myosin heavy chain that we have previously reported to be a molecular marker of dedifferentiated VSMCs. We next examined the role of Hex in SMemb gene transcription. Promoter analysis demonstrated that the sequence identical to consensus cAMP-responsive element (CRE) located at -481 of the SMemb promoter was critical for Hex responsiveness. Mutant Hex expression vector, which lacks the homeodomain, failed to stimulate SMemb gene transcription, suggesting the requirement of the homeodomain for its transactivation. Elecrophoretic mobility shift assay showed that Hex binds to a consensus binding sequence for homeobox proteins, but not to CRE. Cotransfection of protein kinase A expression vector increased the ability of Hex to stimulate SMemb promoter activity in a CRE-dependent manner. Overexpression of CRE binding protein (CREB), but not Mut-CREB which contains mutation at Ser133, strongly activated Hex-induced SMemb promoter activity. These results suggest that Hex mediates transcriptional induction of the SMemb/NMHC-B gene via its homeodomain, and Hex can function as a transcriptional modulator of CRE-dependent transcription in VSMCs.
  • H Morita, H Kurihara, S Yoshida, Y Saito, T Shindo, Y Oh-Hashi, Y Kurihara, Y Yazaki, R Nagai
    Circulation 103(1) 133-9 2001年1月2日  査読有り
    BACKGROUND: Increasing evidence indicates that elevated plasma homocysteine levels are associated with an increased risk of atherosclerosis and endothelial dysfunction, although little specific information on the mechanisms responsible for the atherogenic effects of homocysteine or on the in vivo contribution made by hyperhomocysteinemia to atherosclerosis is currently available. Because homocysteine is known to exert a direct inhibitory effect on endothelial cell growth in vitro, we hypothesized that this effect contributes to the progression of atherosclerotic lesions initiated by endothelial damage caused by mechanical injury. METHODS AND RESULTS: We prepared diet-induced hyperhomocysteinemic rats in which neointima formation after balloon injury to the common carotid artery was assessed. Moderate hyperhomocysteinemia (plasma homocysteine levels 3- to 4-fold higher than control) significantly exacerbated neointima formation. Oral administration of folate, which had a homocysteine-lowering effect, diminished neointima formation induced by moderate hyperhomocysteinemia. Furthermore, the attenuation of reendothelialization was shown in diet-induced hyperhomocysteinemic rats with Evans blue staining. CONCLUSIONS: Diet-induced hyperhomocysteinemia, even mild to moderate, exacerbates neointima formation after denuding injury, making hyperhomocysteinemia a likely risk factor for postangioplasty restenosis. It may be mediated through an inhibitory effect of homocysteine on reendothelialization. Homocysteine lowering with folate supplementation can effectively ameliorate the detrimental effects of moderate hyperhomocysteinemia. Clinical trials would seem to be warranted.
  • H. Iwasa, M. Kurabayashi, R. Nagai, Y. Nakamura, T. Tanaka
    Journal of Human Genetics 46(9) 549-552 2001年  
    We provide here 29 genetic variations, including 28 novel ones, in five genes that are potentially involved in the excitement of cardiomyocytes: we found 4 in KCNA10, 2 in KCNK1, 8 in KCNK6, 11 in SLC18A1 (VMAT1), and 4 in SLC6A2 (norepinephrine transporter). We also examined their allelic frequencies in a Japanese population of long QT syndrome-affected and nonaffected individuals. These data would be useful for genetic association studies designed to investigate acquired arrhythmias.
  • 鹿毛 秀宣, 飯田 陽子, 石坂 信和, 中村 文隆, 高橋 利之, 大野 実, 平田 恭信, 小室 一成, 永井 良三
    Japanese circulation journal 65(7) 593-598 2001年  
  • K Maemura, MD Layne, M Watanabe, MA Perrell, R Nagai, ME Lee
    ATHEROSCLEROSIS VI 947 398-402 2001年  
    We recently isolated a novel bHLH/PAS protein, CLIF (cycle like factor), by yeast two-hybrid screening of human umbilical endothelial cell cDNA library. CLIF is preferentially expressed in endothelial and neuronal cells. Because CLIF is expressed in vascular endothelial cells and forms a heterodimer with CLOCK, the key transcription factor controlling the circadian rhythm, we hypothesized that CLIF regulates the circadian oscillation of PAI-1 gene expression in endothelial cells. Northern blot analysis of mouse organs showed circadian oscillations of PAI-1 mRNA levels. In addition, the clock-related genes also showed circadian oscillation in peripheral tissues. In endothelial cells, the heterodimer of CLIF and CLOCK upregulated the PAI-1 gene expression through E-box sites. Furthermore, Period and Cryptochrome, which are negative regulators in the feedback loop of the biological clock, inhibited PAI-1 promoter activation by the CLOCK:CLIF heterodimer. These results suggest that the peripheral tissues have their own biological clock and CLIF regulates the circadian oscillation of PAI-1 gene expression in endothelial cells. This study suggests a novel molecular mechanism of the morning onset of myocardial infarction. Here we review our recent work and literature.
  • Y Imai, T Shindo, K Maemura, Y Kurihara, R Nagai, H Kurihara
    ATHEROSCLEROSIS VI 947 26-34 2001年  
    Adrenomedullin (AM) has been implicated as having hypotensive as well as protective effects on organs and vessels against different kinds of injuries. To elucidate the in vivo pathophysiological roles of adrenomedullin, we established transgenic mice (AMTg) overexpressing adrenomedullin driven by preproendothelin-1 promoter and adrenomedullin knockout mice (AMKO). Blood pressure in AMTg was significantly lower than that in wild-type mice, and AMTg was significantly resistant to lipopolysaccharide-induced septic shock and vascular injuries. On the other hand, heterozygotes of AMKO, AM(+/-), were fully viable and hypertensive as compared with wild littermates. Mice homozygous for adrenomedullin null mutation (AM-/-) were embryonic lethal, and no embryos could survive beyond the midterm of gestation. Collectively, our findings Indicate the indispensable role of adrenomedullin in circulatory homeostasis and the organ protection as well as the fetal morphogenesis and the maintenance of pregnancy.
  • T Takahashi, Y Sugishita, K Kinugawa, T Shimizu, A Yao, K Harada, H Matsui, R Nagai
    MOLECULAR AND CELLULAR BIOCHEMISTRY 226(1-2) 57-65 2001年  
    In order to elucidate roles of Ets family of transcription factors in transcriptional activation of inducible nitric oxide synthase (iNOS) genes, we analyzed the chick iNOS gene expression in cultured chick embryonic ventricular myocytes (CEVM). Deletional analysis and site-directed mutagenesis demonstrated that both the Ets/PEA3 site (-221 to -216 bp) and the kappaB site (-101 to -93 bp) of the 5'-flanking region of the chick iNOS gene were involved in the maximal activation of the lipopolysaccharide (LPS)-induced expression of the reporter (luciferase) gene, although the proximal kappaB site played the more essential role. Electrophoretic mobility shift assay revealed that LPS augmented the nuclear protein bindings to the Ets/PEA3 as well as kappaB motifs. Ets-1, one of the Ets proteins, was suggested to be bound to the Ets/PEA3 oligonucleotide. By Northern blot analysis, LPS was shown to induce iNOS mRNA in CEVM, along with a preceding increase in the levels of c-ets-1 mRNA. Ets-1 may be involved in the iNOS gene transcription in CEVM, presumably through interacting with the NF-kappaB.
  • Y. Mitani, M. Ueda, R. Komatsu, K. Maruyama, R. Nagai, M. Matsumura, M. Sakurai
    European Respiratory Journal 17(2) 316-320 2001年  
    Primary pulmonary hypertension (PPH) is associated with specific structural alterations, including cellular intimal thickening, intimal fibrosis, and plexiform lesions. To determine the phenotypes of smooth muscle cells (SMCs) in such lesions, the authors conducted an immunohistochemical analysis of lung tissues from two patients with PPH, using two antimuscle actin antibodies, HHF35 and CGA7, and two anti-SMC myosin heavy chain markers, anti-SM1 and anti-SM2 antibodies and related antibodies. Cells that stained positive (+) with HHF35, CGA7, anti-SM1, and anti-SM2 were considered to be SMCs of a mature state. Conversely, those that stained positive with HHF35 and anti-SM1, but weakly positive (+/-) or negative (-) with CGA7 and anti-SM2, were considered to be SMCs exhibiting an immature state. Cellular intimal thickening was composed of SMCs of an immature phenotype (HHF35+, CGA7+/-, SM1+, SM2+/-), accompanied by the expression of fibronectin and the presence of macrophages intimal fibrosis contained mature SMCs (HHF35+, CGA7+, SM1+, SM2+) and plexiform lesion consisted of proliferative endothelial cells (von Willebrand factor-positive cells, proliferating cell nuclear antigen-positive cells) and underlying immature SMCs (HHF35+, CGA7-, SM1+, SM2-) associated with fibronectin expression and macrophage infiltration. These findings suggest that smooth muscle cells with specific phenotypes may contribute to the development of specific vascular lesions in primary pulmonary hypertension.
  • H Iwasa, M Kurabayashi, R Nagai, Y Nakamura, T Tanaka
    JOURNAL OF HUMAN GENETICS 46(3) 158-162 2001年  
    We report here 20 single-nucleotide polymorphisms (SNPs), including 15 novel ones, in six genes that are considered to be candidates for long QT syndrome (LQTS): 2 SNPs in KCNB1, 3 in KCND3, 3 in KCNJ11, 7 in ABCC9, 3 in ADRB1, and 2 in SLC18A2. We also examined their allelic frequencies in a Japanese sample population of LQTS-affected and nonaffected individuals. These data will be useful for genetic association studies designed to investigate acquired arrhythmias.
  • T Itoh, K Kikuchi, Y Odagawa, S Takata, K Yano, S Okada, N Haneda, S Ogawa, O Nakano, Y Kawahara, H Kasai, T Nakayama, T Fukutomi, H Sakurada, A Shimizu, Y Yazaki, R Nagai, Y Nakamura, T Tanaka
    JOURNAL OF HUMAN GENETICS 46(1) 38-40 2001年  
    Mutations in any of the five genes KCNQ1, KCNH2, KCNE1, KCNE2, and SCN5A can be responsible for familial long QT syndrome (LQTS), an arrhythmogenic disorder that entails a high risk of sudden death. beta -Adrenergic blocking agents are the first therapeutic choice, and 80% of patients treated with these agents show symptomatic relief; however the remaining 20% do not respond well. We previously performed a nationwide analysis of familial long QT syndrome (LQTS) in Japan and identified 32 mutations in the KCNQ1 and KCNH2 genes. In the present retrospective study, we found that patients carrying mutations in the KCNQ1 gene responded better to beta -adrenergic blocking agents than these with KCNH2 mutations (12 of 13 vs 1 of 5; P = 0.0077, Fisher's exact test). This is a good example of the power of genetic diagnosis to direct the selection of appropriate therapy for patients with diseases of heterogeneous genetic etiology.
  • Yumiko Oishi, Yoshichika Sando, Syunji Tajima, Toshitaka Maeno, Yuri Maeno, Mahito Sato, Tatsuya Hosono, Tatsuo Suga, Masahiko Kurabayashi, Ryozo Nagai
    Respirology 6(1) 57-60 2001年  
    Indomethacin is one of the most popular non-steroidal anti-inflammatory drugs (NSAID). Although NSAID occasionally provoke bronchospasm and hypersensitivity pneumonia, they seldom cause lymphadenopathy. This is the first report in which NSAID induced both eosinophilic pneumonia and bulky intrathoracic lymphadenopathy simultaneously. A 76-year-old Japanese man experienced high fever and dyspnoea after using an indomethacin suppository. Computed tomography scan of his chest revealed massive mediastinal and hilar lymphadenopathy along with diffuse infiltration in both lungs. He was diagnosed to have eosinophilic pneumonia because of eosinophilia in his peripheral blood and bronchoalveolar lavage fluid (BALF). Without using glucocorticoids, the pulmonary infiltration and lymphadenopathy subsided spontaneously. As the blastoid transformation test using the lymphocytes in his BALF was positive to indomethacin, we judged that both his eosinophilic pneumonia and mediastinal lymphadenopathy were due to a hypersensitivity reaction to indomethacin. An allergic reaction to NSAID should be considered as a rare cause of mediastinal lymphadenopathy.
  • T Iwasaki, T Iwasaki, Y Aihara, T Kanda, N Oriuchi, K Endo, H Katoh, T Suzuki, R Nagai
    Journal of nuclear medicine : official publication, Society of Nuclear Medicine 42(1) 130-7 2001年1月  査読有り
    UNLABELLED: Aortic dissection is among the most common of fatal conditions of the aorta. Prompt and accurate diagnosis of the site and extent of the lesion is necessary for adequate therapy. However, this catastrophic disease, characterized by extensive damage to smooth muscle cells, lacks specific signs and symptoms. As a result, the diagnosis is still frequently missed today and a new diagnostic method to specifically identify aortic dissection would be attractive. The purpose of this study was to examine the feasibility of radioimmunoscintigraphy using 99mTc-anti-smooth muscle myosin monoclonal antibody (SM-MAb) for the noninvasive diagnosis of aortic dissection in the rat experimental model. METHODS: The accumulation of 99mTc-anti-SM-MAb was studied, and scintigraphic imaging with 99mTc-anti-SMMAb was performed in rats immediately after experimental aortic dissection and 1 and 2 wk later. RESULTS: The radioactivity of 99mTc-anti-SM-MAb in the dissected aorta showed a significant increase compared both with the normal portion of the aorta and with blood 6 h after injection of the radiotracer; the ratio of the percentage injected dose per gram (%lD/g) in the lesion to that retained in the normal portion was 4.17 +/- 1.47. Scintigraphic imaging with 99mTc-anti-SM-MAb allowed distinct visualization of the dissected aorta with specific accumulation of antibody 6 h after tracer injection. Selective accumulation of the tracer in the dissected portion of the aorta persisted even 1 wk after aortic injury, allowing clear visualization of the dissected lesion by scintigraphy. CONCLUSION: Radioimmunoscintigraphy using anti-SM-MAb is a potentially useful noninvasive diagnostic method for imaging aortic dissection.
  • T Itoh, K Kikuchi, Y Odagawa, S Takata, K Yano, S Okada, N Haneda, S Ogawa, O Nakano, Y Kawahara, H Kasai, T Nakayama, T Fukutomi, H Sakurada, A Shimizu, Y Yazaki, R Nagai, Y Nakamura, T Tanaka
    Journal of human genetics 46(1) 38-40 2001年  査読有り
    Mutations in any of the five genes KCNQ1, KCNH2, KCNE1, KCNE2, and SCN5A can be responsible for familial long QT syndrome (LQTS), an arrhythmogenic disorder that entails a high risk of sudden death. beta-Adrenergic blocking agents are the first therapeutic choice, and 80% of patients treated with these agents show symptomatic relief; however the remaining 20% do not respond well. We previously performed a nationwide analysis of familial long QT syndrome (LQTS) in Japan and identified 32 mutations in the KCNQ1 and KCNH2 genes. In the present retrospective study, we found that patients carrying mutations in the KCNQ1 gene responded better to beta-adrenergic blocking agents than those with KCNH2 mutations (12 of 13 vs 1 of 5; P = 0.0077, Fisher's exact test). This is a good example of the power of genetic diagnosis to direct the selection of appropriate therapy for patients with diseases of heterogeneous genetic etiology.
  • H Kanai, T Tanaka, Y Aihara, S Takeda, M Kawabata, K Miyazono, R Nagai, M Kurabayashi
    CIRCULATION RESEARCH 88(1) 30-36 2001年1月  
    Transforming growth factor (TGF)-beta plays a major role in the development of vascular diseases. Despite the pleiotropic effects of TGF-beta on vascular smooth muscle cells (VSMCs), only a few genes have been characterized as direct targets of TGF-beta in VSMCs. Cardiac ankyrin repeat protein (CARP) has been thought to be expressed exclusively in the heart. In the present study, we showed that CARP is expressed in the vasculature after balloon injury and in cultured VSMCs in response to TGF-beta. Analysis of a half-life of the cytoplasmic CARP mRNA levels and the transient transfection of the CARP promoter/luciferase gene indicates that the regulation of CARP expression is increased by TGF-beta at the transcriptional level. Transfection of expression vectors encoding Smads significantly activated the CARP promoter/luciferase activity. Deletion analysis and site-specific mutagenesis of the CARP promoter indicate that TGF-beta response element is localized to CAGA motif at -108 bp relative to the transcription start site. Electrophoretic mobility shift assays showed that the binding activity to the CAGA motif was increased in nuclear extracts of cultured VSMCs by TGF-beta. Cells transfected with adenovirus vector expressing CARP showed a significant decrease in DNA synthesis. Overexpression of CARP enhanced the TGF-beta -mediated inhibition of the DNA synthesis. These data indicate that CARP is a downstream target of TGF-beta /Smad signaling in VSMCs and suggest a role of CARP in mediation of the inhibitory effects of TGF-beta on the proliferation of VSMCs.
  • T Ogata, M Kurabayashi, Y I Hoshino, K I Sekiguchi, K Kawai-Kowase, S Ishikawa, Y Morishita, R Nagai
    Transplantation 70(11) 1653-6 2000年12月15日  査読有り
    BACKGROUND: We have recently identified basic transcription factor-binding protein 2 (BTEB2), which is involved in phenotypic modulation of vascular vascular smooth muscle cells. The aim of this study was to investigate the expression of BTEB2 in cardiac allograft vascular disease. METHODS: Heterotopic cardiac transplantation was performed in rats. All grafts were stained with antibodies against for BTEB2 and cyclin-dependent kinase 4 for immunohistochemical study. The intensity of BTEB2 expression was also calculated. RESULTS: In the allografts at 4 and 8 weeks after transplantation, smooth muscle cells were positive for BTEB2 in the diffusely thickened coronary arteries and the perivascular space. BTEB2 expression was closely associated with cyclin-dependent kinase 4 expression. The BTEB2 expression score was significantly higher in the allografts compared with the isografts. CONCLUSIONS: The induced expression of BTEB2 may play a potential role in the development of the cardiac allograft vascular disease.
  • R Aikawa, M Nawano, Y Gu, H Katagiri, T Asano, W Zhu, R Nagai, I Komuro
    Circulation 102(23) 2873-9 2000年12月5日  査読有り
    BACKGROUND: Loss of cardiomyocytes by apoptosis is proposed to cause heart failure. Reactive oxygen species induce apoptosis in many types of cells including cardiomyocytes. Because insulin has been reported to have protective effects, we examined whether insulin prevents cardiomyocytes from oxidative stress-induced apoptotic death. METHODS AND RESULTS: Cultured cardiomyocytes of neonatal rats were stimulated by hydrogen peroxide (H(2)O(2)). Apoptosis was evaluated by means of the TUNEL method and DNA laddering. Incubation with 100 micromol/L H(2)O(2) for 24 hours increased the number of TUNEL-positive cardiac myocytes (control, approximately 4% versus H(2)O(2), approximately 23%). Pretreatment with 10(-)(6) mol/L insulin significantly decreased the number of H(2)O(2)-induced TUNEL-positive cardiac myocytes (approximately 12%) and DNA fragmentation induced by H(2)O(2). Pretreatment with a specific phosphatidylinositol 3 kinase (PI3K) inhibitor, wortmannin, and overexpression of dominant negative mutant of PI3K abolished the cytoprotective effect of insulin. Insulin strongly activated both PI3K and the putative downstream effector AKT: Moreover, a proapoptotic protein, BAD:, was significantly phosphorylated and inactivated by insulin through PI3K. CONCLUSIONS: These results suggest that insulin protects cardiomyocytes from oxidative stress-induced apoptosis through the PI3K pathway.

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共同研究・競争的資金等の研究課題

 91