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  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
  • K Harada, M Sonoda, H Nishimura, K Takenaka, R Nagai, T Takahashi
    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 39(5) 377A-377A 2002年3月  
  • K Uno, K Takenaka, S Sakurai, M Asakawa, A Kikuchi, M Matsuzaki, T Takahashi, K Nakahara, R Nagai
    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 39(5) 389A-389A 2002年3月  
  • 西松寛明, 鈴木越, 里中弘志, 長田太助, 佐田政隆, 藤田敏郎, 永井良三, 北村唯一, 平田恭信
    血圧 9(3) 335-339 2002年3月1日  
  • Hitoshi Oonuma, Kuniaki Iwasawa, Haruko Iida, Taiji Nagata, Hiroyuki Imuta, Yutaka Morita, Kazuhiko Yamamoto, Ryozo Nagai, Masao Omata, Toshiaki Nakajima
    American journal of respiratory cell and molecular biology 26(3) 371-9 2002年3月  査読有り
    Inward rectifier K(+) (Kir) channels play an important role in forming membrane potential and then modulating muscle tone in certain types of smooth muscles. In cultured human bronchial smooth muscle cells (hBSMCs), Kir current was identified using whole-cell voltage clamp techniques and explored by using RT-PCR analysis of mRNA, Western blotting, and antisense oligonucleotide methods to block the synthesis of Kir channel protein. The K(+) current with strong inward rectification and high K(+) ion selectivity was observed. The current was unaffected by 4-aminopyridine, glibenclamide, and charybdotoxin, and hardly inhibited by tetraethylammonium, but was potently inhibited by extracellular Ba(2+). The IC(50) value of external Ba(2+) was approximately 1.3 microm. RT-PCR analysis of mRNA showed transcripts for Kir2.1, but not Kir1.1, Kir2.2, or Kir2.3. Treatment of cells with antisense oligonucleotides targeted to Kir2.1 resulted in a decrease in the current density of the Kir current and Kir protein expression, as compared with the mismatch-treated cells, whereas the current density of 4-AP-sensitive K(+) currents (K(V)) remained unaffected. The application of Ba(2+) markedly depolarized the membrane. These results demonstrate that Kir channel is present in human bronchial smooth muscle cells, and the Kir2.1 gene encodes the Kir channel protein in these cells.
  • Nobukazu Ishizaka, Yuko Ishizaka, Eiko Takahashi, Ei-Ichi Tooda, Hideki Hashimoto, Ryozo Nagai, Minoru Yamakado
    Journal of Cardiology 39(3) 151-157 2002年3月  
    Objectives. Serum calcium level may be associated with the morbidity and mortality of cerebrovascular and cardiovascular diseases. However, only a few large-scale population studies have been performed to investigate the association between serum calcium and carotid plaque. Methods. A retrospective cross-sectional study was performed on the subjects who underwent general health screening tests including ultrasonographic evaluation of the carotid artery between 1994 and 2000 at our institute. Before the statistical analysis, all serum calcium values were adjusted for the serum albumin concentration. Results. Of 5,732 subjects enrolled in the present study, 3,785 were male and 1,947 were female, and were aged 22-88 years (median 57 years). Carotid plaque was identified in 1,313 (23%) subjects. Serum calcium concentration was slightly greater in the subjects with plaque than in those without (2.28 ± 0.8 vs 2.27 ± 0.7 mmol/l, p &lt 0.001 unpaired t-test). Multivariate logistic regression analysis including confounding risk factors revealed that serum calcium is an independent positive predictor for carotid plaque with an odds ratio of 1.70 [95% confidence interval (CI): 1.50-1.92] for each increase of 1 mg/dl. Male and female subjects in the highest quartiles of serum calcium concentrations had a greater risk of carotid plaque with odds ratios of 1.52 (95% CI 1.35-1.71, p &lt 0.01) and 1.57 (95% CI 1.27-1.92, p &lt 0.05), respectively, compared to the subjects in the lowest quartiles of calcium concentrations. Conclusions. These findings indicate that serum calcium is an independent risk factor for carotid plaque.
  • N Ishizaka, Y Ishizaka, E Takahashi, E Toda, H Hashimoto, M Ohno, R Nagai, M Yamakado
    CIRCULATION 105(9) 1028-1030 2002年3月  
    Background-Recent experimental and epidemiological findings suggest that some infectious agents play a role in the development and promotion of atherosclerosis. We have investigated the possible association between hepatitis B virus surface antigen (HBsAg) positivity and carotid arteriosclerosis. Methods and Results-In this cross-sectional cohort study, we analyzed data from subjects undergoing general health-screening tests, including both high-resolution B-mode carotid ultrasound and assessment of HBsAg status, between 1994 and 2001 at our institute. Of the 4686 study subjects (3 137 men and 1549 women; age 22 to 88 years), 1294 (28%) had carotid artery plaque and 40 (0.9%) were positive for HBsAg, indicating they were hepatitis B virus carriers. No HBsAg-positive subjects were positive either for antibodies against the hepatitis C virus (HCV) or for HCV core proteins. Univariate analysis revealed HBsAg positivity was associated with carotid plaque with an odds ratio of 1.58 (95% CI, 1.14 to 2.19, P&lt;0.05). When other confounding risk-factors for atherosclerosis were included as covariates in the statistical analysis, HBsAg positivity was still positively associated with carotid plaque with an odds ratio of 1.57 (95% CI. 1.10 to 2.24, P&lt;0.05). Conclusions-These findings suggest a possible role of chronic hepatitis B infection in the pathogenesis of carotid arteriosclerosis.
  • N Takeda, Yokoyama, I, Y Hiroi, M Sakata, T Harada, F Nakamura, Y Murakawa, R Nagai
    CIRCULATION 105(9) 1144-1145 2002年3月  
  • E Takimoto, A Yao, H Toko, H Takano, M Shimoyama, M Sonoda, K Wakimoto, T Takahashi, H Akazawa, M Mizukami, T Nagai, R Nagai, Komuro, I
    FASEB JOURNAL 16(3) 2002年3月  
    The Na+-Ca2+ exchanger (NCX) on the plasma membrane is thought to be the main calcium extrusion system from the cytosol to the extracellular space in many mammalian excitable cells, including cardiac myocytes. However, the pathophysiological role of NCX in the heart is still unclear because of the lack of known specific inhibitors of NCX. To determine the role of NCX in cardiac contraction and the development of cardiac hypertrophy, we imposed pressure overload on the heart of heterozygous NCX knockout (KO) mice by constricting transverse aorta, and examined cardiac function and morphology 3 wk after operation. Although there was no difference in cardiac function between sham-operated KO mice and sham-operated wild-type (WT) mice, KO mice showed higher left ventricular pressure and better systolic function than WT mice in response to pressure overload. Northern blot analysis revealed that mRNA levels of sarcoplasmic reticulum Ca2+-ATPase were reduced by pressure overload in left ventricles of WT but not of KO mice. However, hypertrophic changes with interstitial fibrosis were more prominent in KO mice than WT mice. These results suggest that reduction of NCX results in supernormalized cardiac function and causes marked cardiac hypertrophy in response to pressure overload.
  • Yuko Oyama, Nobuhiro Akuzawa, Ryozo Nagai, Masahiko Kurabayashi
    Circulation research 90(3) 348-55 2002年2月22日  査読有り
    Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily that acts as a key player in adipocyte differentiation, glucose metabolism, and macrophage differentiation. Osteopontin (OPN), a component of extracellular matrix, is elevated during neointimal formation in the vessel wall and is synthesized by macrophages in atherosclerotic plaques. In the present study, we investigated the molecular mechanisms regulating OPN gene expression by PPARgamma in THP-1 cells, a cell line derived from human monocytic leukemia cells. Northern and Western blot analyses showed that exposure of THP-1 cells to PMA (phorbol 12-myristate 13-acetate) increases OPN mRNA and protein levels in a time-dependent manner. PMA-induced OPN expression was significantly decreased by troglitazone (Tro) and other PPARgamma ligands. Transient transfection assays of the human OPN promoter/luciferase construct showed that PPARgamma represses OPN promoter activity, and the PPARgamma-responsive region within the OPN promoter lies between -1000 and -970 relative to the transcription start site. Site-specific mutation analysis and electrophoretic mobility shift assays indicated that a homeobox-like A/T-rich sequence between -990 and -981, which functions as a binding site for PMA-induced nuclear factors other than PPARgamma, mediates the repression of OPN expression by Tro. Furthermore, concatenated A/T-rich sequences conferred the PPARgamma responsiveness on the heterologous promoter. Taken together, these data suggest that PPARgamma ligand inhibits OPN gene expression through the interference with the binding of nuclear factors to A/T-rich sequence in THP-1 cells.
  • 綾部 征司, 大野 実, 永井 良三
    呼吸と循環 50(2) 193-198 2002年2月  
  • Toshimasa Yamauchi, Yuichi Oike, Junji Kamon, Hironori Waki, Kajuro Komeda, Atsuko Tsuchida, Yukari Date, Meng-Xian Li, Hiroshi Miki, Yasuo Akanuma, Ryozo Nagai, Satoshi Kimura, Takeyori Saheki, Masamitsu Nakazato, Takeshi Naitoh, Kenichi Yamamura, Takashi Kadowaki
    Nature genetics 30(2) 221-6 2002年2月  査読有り
    The CBP protein (cAMP response element binding protein (CREB) binding protein) is a co-activator for several transcription factors with a wide range of important biological functions, such as sterol regulatory element binding proteins (SREBPs), CCAAT/enhancer-binding proteins (C/EBPs), nuclear receptors (including peroxisome proliferator-activated receptors, PPARs), and signal transducers and activators of transcription (STATs). In contrast to these individual transcription factors, the biological roles of CBP are poorly understood. CBP enhances transcriptional activities via histone acetylation and the recruitment of additional co-activators such as SRC (steroid coactivator)-1 (ref. 9). To identify its physiological functions using a loss-of-function mutant, we analyzed CBP-deficient mice. As Crebbp null mice (Crebbp-/-) died during embryogenesis, we used Crebbp+/- mice. Unexpectedly, Crebbp+/- mice showed markedly reduced weight of white adipose tissue (WAT) but not of other tissues. Despite this lipodystrophy, Crebbp+/- mice showed increased insulin sensitivity and glucose tolerance and were completely protected from body weight gain induced by a high-fat (HF) diet. We observed increased leptin sensitivity and increased serum adiponectin levels in Crebbp+/- mice. These increased effects of insulin-sensitizing hormones secreted from WAT may explain, at least in part, the phenotypes of Crebbp+/- mice. This study demonstrates that CBP may function as a 'master-switch' between energy storage and expenditure.
  • Kazuo Hara, Philippe Boutin, Yasumichi Mori, Kazuyuki Tobe, Christian Dina, Kazuki Yasuda, Toshimasa Yamauchi, Shuichi Otabe, Terumasa Okada, Kazuhiro Eto, Hiroko Kadowaki, Ryoko Hagura, Yasuo Akanuma, Yoshio Yazaki, Ryozo Nagai, Matsuo Taniyama, Koichi Matsubara, Madoka Yoda, Yasuko Nakano, Motowo Tomita, Satoshi Kimura, Chikako Ito, Philippe Froguel, Takashi Kadowaki
    Diabetes 51(2) 536-40 2002年2月  査読有り
    An adipocyte-derived peptide, adiponectin (also known as GBP28), is decreased in subjects with type 2 diabetes. Recent genome-wide scans have mapped a diabetes susceptibility locus to chromosome 3q27, where the adiponectin gene (APM1) is located. Herein, we present evidence of an association between frequent single nucleotide polymorphisms at positions 45 and 276 in the adiponectin gene and type 2 diabetes (P = 0.003 and P = 0.002, respectively). Subjects with the G/G genotype at position 45 or the G/G genotype at position 276 had a significantly increased risk of type 2 diabetes (odds ratio 1.70 [95% CI 1.09-2.65] and 2.16 [1.22-3.95], respectively) compared with those having the T/T genotype at positions 45 and 276, respectively. In addition, the subjects with the G/G genotype at position 276 had a higher insulin resistance index than those with the T/T genotype (1.61 +/- 0.05 vs. 1.19 +/- 0.12, P = 0.001). The G allele at position 276 was linearly associated with lower plasma adiponectin levels (G/G: 10.4 +/- 0.85 microg/ml, G/T: 13.7 +/- 0.87 microg/ml, T/T: 16.6 +/- 2.24 microg/ml, P = 0.01) in subjects with higher BMIs. Based on these findings together with the observation that adiponectin improves insulin sensitivity in animal models, we conclude that the adiponectin gene may be a susceptibility gene for type 2 diabetes.
  • Toshitaka Maeno, Toru Tanaka, Yoshichika Sando, Tatsuo Suga, Yuri Maeno, Junichi Nakagawa, Tatsuya Hosono, Mahito Sato, Hideo Akiyama, Shoji Kishi, Ryozo Nagai, Masahiko Kurabayashi
    American journal of respiratory cell and molecular biology 26(2) 246-53 2002年2月  査読有り
    In this study, we examined the effects of all trans-retinoic acid (at-RA) on the vascular endothelial growth factor (VEGF) expression in human bronchioloalveolar carcinoma NCI-H322 cells to evaluate the potential of at-RA to affect tumor progression. Northern blot and enzyme-linked immunosorbent assay analyses indicate that VEGF production is significantly increased by 1 microM of at-RA. A series of 5'-deletion and site-directed mutation analyses indicated that G+C-rich sequence located at -81 and -52 was required for at-RA- and retinoic acid receptor alpha-mediated induction of VEGF promoter. Electrophoretic mobility shift and supershift assays showed that major constituents of nuclear factors binding to G+C-rich sequences are Sp1 and Sp3. Pretreatment with cycloheximide, a protein synthesis inhibitor, prevented the at-RA-mediated induction of VEGF mRNA expression. Likewise, at-RA-mediated VEGF expression was completely blocked in the presence of genistein, an inhibitor for tyrosine kinases. These results suggest that an increase in transcription of the VEGF promoter by at-RA is mediated through Sp1 site, and both new protein synthesis and tyrosine kinase activation are necessary for this induction. Because VEGF can promote neovascularization in cancer cells, an induction of VEGF by at-RA may preclude the therapeutic application of at-RA to cancer patients.
  • T Shindo, H Kurihara, K Maemura, Y Kurihara, O Ueda, H Suzuki, T Kuwaki, K-H Ju, Y Wang, A Ebihara, H Nishimatsu, N Moriyama, M Fukuda, Y Akimoto, H Hirano, H Morita, M Kumada, Y Yazaki, R Nagai, K Kimura
    Journal of molecular medicine (Berlin, Germany) 80(2) 105-16 2002年2月  査読有り
    The recent development of endothelin-1 (ET-1) antagonists and their potential use in the treatment of human disease raises questions as to the role of ET-1 in the pathophysiology of such cardiovascular ailments as hypertension, heart failure, renal failure and atherosclerosis. It is still unclear, for example, whether activation of an endogenous ET-1 system is itself the primary cause of any of these ailments. In that context, the phenotypic manifestations of chronic ET-1 overproduction may provide clues about the tissues and systems affected by ET-1. We therefore established two lines of transgenic mice overexpressing the ET-1 gene under the direction of its own promoter. These mice exhibited low body weight, diminished fur density and two- to fourfold increases in the ET-1 levels measured in plasma, heart, kidney and aorta. There were no apparent histological abnormalities in the visceral organs of young (8 weeks old) transgenic mice, nor was their blood pressure elevated. In aged (12 months old) transgenic mice, however, renal manifestations, including prominent interstitial fibrosis, renal cysts, glomerulosclerosis and narrowing of arterioles, were detected. These pathological changes were accompanied by decreased creatinine clearance, elevated urinary protein excretion and salt-dependent hypertension. It thus appears that mild, chronic overproduction of ET-1 does not primarily cause hypertension but triggers damaging changes in the kidney which lead to the susceptibility to salt-induced hypertension.
  • Nobukazu Ishizaka, Haruo Mitani, Ryozo Nagai
    Nippon rinsho. Japanese journal of clinical medicine 60(10) 1935-1939 2002年  
    Regulation of the expression of the klotho gene, which suppresses the expression of multiple aging-associated phenotypes, by angiotensin II was investigated. Continuous infusion of angiotensin II downregulated renal klotho gene expression, which was an AT1 receptor-dependent, but pressor-independent event. In some experiments, adenovirus harboring mouse klotho gene(ad-klotho, 3.3 x 10(10) pfu) was intravenously administered immediately before starting angiotensin II infusion, and this resulted in an improvement of creatinine clearance, decrease in urinary protein excretion, and amelioration of tubulointerstitial damage induced by this octapeptitde. Downregulation of the renal klotho gene may have a role in the development of angiotensin II-induced end organ damage.
  • H Sugi, S Yasuda, S Sugiura, H Yamashita, K Katoh, Y Saeki, H Kaneko, Y Suda, R Nagai
    BIOPHYSICAL JOURNAL 82(1) 596A-596A 2002年1月  査読有り
  • 斎藤 勇一郎, 永井 良三
    現代医療 34(4) 2698-2702 2002年  
  • 藤生克仁, 中島敏明, 山崎正雄, 中村文隆, 園田誠, 世古義規, 高橋利之, 大野実, 永井良三
    日本内科学会関東地方会 500th 2002年  
  • 佐藤愛, 西村剛, 都島健介, 前村浩二, 村川裕二, 園田誠, 中村文隆, 大野実, 永井良三
    Circulation Journal 66 2002年  
  • 森田敏宏, 中村文隆, 山崎正雄, 小早川直, 藤本肇, 中島敏明, 大野実, 平田恭信, 永井良三
    Japanese Journal of Interventional Cardiology 17(Supplement 1) 2002年  
  • M Ohno, XB Yu, S Ayabe, R Nagai
    FREE RADICAL BIOLOGY AND MEDICINE 33 S336-S336 2002年  
  • Y Zou, Komuro, I, A Yao, W Zhu, S Kudoh, Y Hiroi, M Shimoyama, H Uozumi, T Takahashi, R Nagai, Y Yazaki, O Kohmoto, F Shibasaki
    CIRCULATION 105(2) E9-E9 2002年1月  
  • K Yonekura, Yokoyama, I, T Ohtake, Y Inoue, T Aoyagi, S Sugiura, T Momose, Otomo, I, R Nagai
    JOURNAL OF NUCLEAR CARDIOLOGY 9(1) 62-67 2002年1月  
    Background. Decreased myocardial flow reserve (MFR) in angiographically normal coronary arteries in patients with old myocardial infarction (OMI) has been reported. Methods and Results. To clarify factors for the reduced MFR in OMI and to compare them with those in angina pectoris (AP), baseline myocardial blood now (MBF) and MBF during dipyridamole administration were measured with nitrogen 13 ammonia positron emission tomography, after which MFR was calculated for 13 men with AP, 18 men with OMI, and 15 age-matched male control subjects. MFR was compared among the 3 groups in segments perfused by nonstenotic arteries. Baseline MBF in patients with OMI was significantly higher than that in patients with AP and control subjects. MBF during dipyridamole administration in patients with OMI was significantly lower than that in control subjects. MFR in patients with AP was 2.50+/-0.91 (P&lt;.05 vs control subjects [3.47&PLUSMN;1.25]), and that in patients with OMI was 1.83&PLUSMN;0.61 (P&lt;.01 vs control and AP groups). Ejection fraction (EF) in patients with OMI was significantly decreased compared with that in patients with AP. However, there was no significant difference in the mean score of the individual risk factors between patients with AP and those with OMI. In the pooled data with AP and OMI, baseline MBF and EF were significant for the reduced MFR. Conclusions. MFR and EF in patients with OMI were significantly decreased compared with those in patients with AP. Increased baseline MBF and decreased EF were significant factors for the reduced MFR in patients with AP and OMI.
  • 佐田 政隆, 平田 恭信, 永井 良三
    Journal of cardiology 39(1) 48-9 2002年1月  査読有り
  • 西松 寛明, 鈴木 越, 里中 弘志, 長田 太助, 鹿子木 将夫, 早川 宏, 後藤 淳郎, 北村 唯一, 永井 良三, 藤田 敏郎
    血管 25(1) 18-18 2002年1月  
  • T. Yamazaki, Suzuki, R. Shimamoto, T. Tsuji, T. Nakajima, R. Nagai, S. Komatsu, K. Otomo, T. Toyo-Oka, M. Omata
    Radiography 8(3) 181-187 2002年  
    Purpose: Exposure time within 40 ms for chest radiography is brief, and therefore cardiac timing of exposure may influence cardio-thoracic ratio (CTR). To determine whether or not ECG triggering is required, it is necessary to evaluate the cardiac size during the complete cardiac cycle. Methods: A ciné magnetic resonance series was obtained in eight contiguous coronal planes in ten patients. At a single cardiac phase, the maximum horizontal length from the middle to the right cardiac border was measured on each coronal image. The transverse diameter to the right border of the cardiac silhouette projected on the imaginary radiograph was defined as the greatest value of length obtained by magnifying the eight maximum horizontal lengths in inverse projection to the distance from the imaginary X-ray source to each imaging plane. The transverse diameter to the left border was also defined. The two diameters were then summed to describe the cardiac size at the common cardiac phase. To constitute cardiac phase-cardiac size curves this procedure was repeated for eight cardiac phases. Results: On cardiac phase-cardiac size curves, the maximum transverse silhouette of the heart (diameter: 155 ± 15 mm) was obtained at a delay time of 0 ms from R wave and the minimum size (diameter: 149 ± 16 mm) was identified at a delay time of 240 ms in all patients. Conclusions: Although the fluctuation of the size of the projected cardiac silhouette during a cardiac cycle was statistically significant, the fluctuation magnitude of 2% indicated clinical acceptability of chest radiography without electrocardiographic gating. © 2002 The College of Radiographers. Published by Elsevier Science Ltd. All rights reserved.
  • Nobukazu Ishizaka, Norihide Kage, Haruko Iida, Shinsuke Mutoh, Yasunobu Hirata, Issei Komuro, Takeshi Miyairi, Tadashi Kitamura, Tetsuro Morota, Shinichi Takamoto, Ryozo Nagai
    Cardiology 97(1) 53-4 2002年  査読有り
  • YZ Zou, T Yamazaki, K Nakagawa, H Yamada, N Iriguchi, H Toko, H Takano, H Akazawa, R Nagai, Komuro, I
    HYPERTENSION RESEARCH 25(1) 117-124 2002年1月  
    We examined whether Ca2+ channel blockers inhibit the activation of the Ca2+-dependent phosphatase calcineurin and the development of cardiac hypertrophy in spontaneously hypertensive rats (SHR). We randomly divided 12-week-old SHR into three groups, one each receiving vehicle, bolus injection or continuous infusion of nifedipine (10 mg/kg/day) from 12 to 24 weeks of age. Systolic blood pressure (1313) and heart rate were measured every week after the treatment using the tall-cuff plethysmography method. After 4, 8 and 12 weeks of treatment, 6 rats of each group were subjected to examinations that included an assay for calcineurin activity in the heart, magnetic resonance imaging (MRI), histology and Northern blot analysis. Continuous infusion of nifedipine consistently reduced BID, whereas bolus injection resulted in a fluctuation of BP. Continuous infusion of nifedipine not only reduced left ventricular mass but also decreased the transverse diameter of cardiomyocytes, interstitial fibrosis and the expression of the atrial natriuretic peptide and brain natriuretic peptide genes in the heart, while bolus injection of nifedipine did not significantly attenuate any of these hypertrophic responses in SHR. The activity of calcineurin in the heart was strongly suppressed by continuous but not bolus infusion of nifedipine in SHR. The results indicate that continuous blockade of Ca2+ channels with nifedipine effectively suppresses the development of cardiac hypertrophy in SHR, possibly through inhibition of the calcineurin activity.
  • Journal of Sports Science and Medicine 4 141-146 2002年  
  • Recent Res. Devel. Immunology 4, 227-233 2002年  
  • Hiroyasu Iwasa, Masahiko Kurabayashi, Ryozo Nagai, Yusuke Nakamura, Toshihiro Tanaka
    Journal of human genetics 47(4) 208-12 2002年  査読有り
    We here report 20 novel single-nucleotide polymorphisms in four genes that are potentially involved in the excitement of cardiomyocytes: 1 in KCNA5 (encoding Kv1.5), 5 in KCNAB1 (encoding Kvbeta1.3), 5 in KCNIP2 (encoding KChIP2), and 9 in CACNA1C (encoding a cardiac L-type voltage-dependent calcium ion channel, dihydropyridine receptor). We also examined their allelic frequencies in Japanese individuals. These data will be useful for genetic association studies designed to investigate secondary long QT syndrome or other circulatory disorders.
  • T Harada, T Aoyagi, Y Endo, K Uno, K Takenaka, F Nakamura, M Sonoda, T Takahashi, T Yamazaki, Y Hiroi, M Ohno, Y Hirata, R Nagai
    ANGIOLOGY 53(1) 105-108 2002年1月  
    A 59-year-old man had a history of rheumatoid arthritis. lie presented with incurable pericardial effusion. He was repeatedly treated With pericardiocentesis with only transient attenuation of his symptoms because the underlying pericardial constriction had been overlooked. This time the authors diagnosed effusive constrictive pericarditis due to rheumatoid arthritis using the hemodynamic findings observed before and after pericardiocentesis.
  • Hiroyuki Morita, Yuichiro Saito, Masahiko Kurabayashi, Ryozo Nagai
    Journal of hypertension 20(1) 55-62 2002年1月  査読有り
    OBJECTIVES: We investigated the influence of hyperhomocysteinemia and high salt intake on sodium handling, oxidative state, vascular endothelial function and blood pressure in a rat model. METHODS: Eight-week-old male Sprague-Dawley rats were divided into subgroups and maintained for 4 weeks prior to experimentation on either control chow containing 0.36% methionine and 0.5% NaCl; or one of the following modified diets containing either 0.7% methionine, 8% NaCl or 0.7% methionine + 8% NaCl. Sodium handling, homocysteine metabolism, lipid profile, NO synthesis, oxidative state, blood pressure and relaxation to acetylcholine of carotid rings were evaluated and compared. RESULTS: Diet-induced mild hyperhomocysteinemia (plasma homocysteine levels 1.4-fold higher than control), by itself, had no significant influence on sodium excretion, vascular endothelial function and blood pressure. Increased salt intake had no influence on homocysteine metabolism, vascular endothelial function and blood pressure. The coexistence of mild hyperhomocysteinemia and high salt intake significantly diminished vascular endothelial function (rmax to acetylcholine; control chow 83.2 +/- 6.2%, 0.7% methionine diet 74.7 +/- 3.9%, 8% NaCl diet 85.1 +/- 4.6%, 0.7% methionine + 8% NaCl diet 57.9 +/- 6.6%) but manifested no rise in blood pressure. No significant difference in oxidative state was observed in this analysis. CONCLUSIONS: Diet-induced mild hyperhomocysteinemia, the extent of which is comparable with the levels that are associated with a predisposition to common atherosclerotic diseases, was found to induce vascular endothelial dysfunction only when accompanied by high salt intake.
  • T Aizawa, N Ishizaka, S Usui, N Ohashi, M Ohno, R Nagai
    HYPERTENSION 39(1) 149-154 2002年1月  
    We investigated the extent of oxidative stress evoked in the hypertensive rat by measuring plasma levels of 8-epi-prostaglandin F-2alpha (8-epi-PGF(2alpha)), a marker of in vivo oxidative stress. Administration of angiotensin (Ang) II and norepinephrine at doses of 0.7 and 2.8 mg . kg(-1) . d(-1), respectively, resulted in similar significant elevations in plasma levels of 8-epi-PGF(2alpha). A 7-day infusion of Ang II at a nonpressor dose, but not norepinephrine at a nonpressor dose, also increased plasma levels of 8-epi-PGF(2alpha). The norepinephrine-induced increase in 8-epi-PGF(2alpha) levels could be completely normalized by 3 different classes of anti hypertensive drugs: prazosin, an alpha-adrenergic receptor blocker; hydralazine, a nonspecific vasodilator; and losartan, a specific angiotensin type 1 (AT(1)) receptor antagonist. This finding suggests that the norepinephrine-induced increase is a pressor-dependent event. In contrast, among these antihypertensive drugs, only losartan was effective in inhibiting the Ang II-induced increase in plasma 8-epi-PGF(2alpha), suggesting that Ang II increases plasma levels of 8-epi-PGF(2alpha) in both a pressor-independent and an AT(1) receptor-dependent manner. In summary, continuous infusion of both Ang II and norepinephrine potently increases plasma levels of 8-epi-PGF(2alpha) and thus in vivo oxidative stress. Ang II and norepinephrine seem to induce this increase in 8-epi-PGF(2alpha) via mechanisms with different pressor dependencies.
  • N Ishizaka, T Aizawa, Yamazaki, I, S Usui, Mori, I, K Kurokawa, SS Tang, Ingelfinger, JR, M Ohno, R Nagai
    LABORATORY INVESTIGATION 82(1) 87-96 2002年1月  
    Acute experimental iron loading causes iron to accumulate in the renal tissue. The accumulation of iron may play a role in enhancing oxidant-induced tubular injury by producing increased amounts of reactive oxygen species. From findings in cells from heme oxygenase-1 (HO-1) -deficient mice, HO-1 is postulated to prevent abnormal intracellular iron accumulation. Recently, it has been reported that HO-1 is induced in the renal tubular epithelial cells, in which iron is deposited after iron loading, and that this HO-1 induction may be involved in ameliorating iron-induced renal toxicity. We previously showed that chronic administration of angiotensin II to rats induces HO-1 expression in the tubular epithelial cells. These observations led us to investigate whether there is a link between iron deposition and HO-1 induction in renal tubular cells in rats undergoing angiotensin II infusion. In the present study, rats were given angiotensin II for continuously 7 days. Prussian blue staining revealed the distinct deposits of iron in the proximal tubular epithelial cells after angiotensin II administration. Electron microscopy demonstrated that iron particles were present in the lysosomes of these cells. Histologic and immunohistochemical analyses showed that stainable iron and immunoreactive ferritin and HO-1 were colocalized in the tubular epithelial cells. Treatment of angiotensin II-infused rats with an iron chelator, deferoxamine, blocked the abnormal iron deposition in kidneys and also the induced expression of HO-1 and ferritin expression. Furthermore, deferoxamine treatment suppressed the angiotensin II-induced increase in the urinary excretion of protein and N-acetyl-beta-D-glucosaminidase, a marker of tubular injury; however, deferoxamine did not affect the angiotensin II-induced decrease in glomerular filtration rate. These results suggest that angiotensin II causes renal injury, in part, by inducing the deposition of iron in the kidney.
  • Mahito Sato, Toru Tanaka, Toshitaka Maeno, Yoshichika Sando, Tatsuo Suga, Yuri Maeno, Hiroko Sato, Ryozo Nagai, Masahiko Kurabayashi
    American journal of respiratory cell and molecular biology 26(1) 127-34 2002年1月  査読有り
    Hypoxia is a potent inducer of tumor angiogenesis, the process of which is mostly mediated by induction of vascular endothelial growth factor (VEGF). In this study, we investigated the effect of hypoxia on the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and endothelial PAS domain protein-1 (EPAS1). These two similar but distinct basic helix-loop-helix-PAS proteins have been postulated to activate VEGF expression in response to hypoxia. We showed that EPAS1, but not HIF-1alpha, is abundantly expressed in human lung adenocarcinoma A549 cells. Exposure of cultured A549 cells to hypoxia increased EPAS1 mRNA and protein levels. A specific inhibitor for Src family kinases, PP1, abolished the hypoxia-induced expression of EPAS1. Transient transfection assays revealed that forced expression of EPAS1 increased the reporter gene activity driven by EPAS1 promoter as well as by VEGF promoter. Finally, overexpression of EPAS1 by infection of adenoviral vector expressing EPAS1 cDNA evidently induced the endogenous EPAS1 gene expression. Together, these data demonstrate Src family kinases mediate the hypoxia-mediated EPAS1 gene expression, which in turn positively autoregulates its own expression. Given an EPAS1 as a potent activator of the VEGF gene, these findings will provide a novel insight into the mechanisms underlying the enhancement of growth property of EPAS1-expressing tumor cells under the hypoxic environment.
  • N Ishizaka, Y Ishizaka, E Takahashi, E Tooda, H Hashimoto, R Nagai, M Yamakado
    LANCET 359(9301) 133-135 2002年1月  
    We Investigated the relation between positivity for hepatitis C virus (HCV) and carotid-artery plaque and carotid intima-media thickening by analysing cross-sectional data of Individuals undergoing a general health screening test. Of 4784 individuals enrolled, 104 (2.2%) were seropositive for HCV. After adjustment for confounding risk factors, HCV seropositivity was found to be associated with an increased risk of carotid-artery plaque (odds ratio 1.92 [95% Cl 1.56-2.38], p = 0.002) and carotid intima-media thickening (2.85 [2.28-3.57], p &lt; 0.0001). These findings suggest a possible role for chronic hepatitis C in the pathogenesis of carotid arterial remodelling.
  • N Ishizaka, T Aizawa, M Ohno, S Usui, Mori, I, SS Tang, Ingelfinger, JR, S Kimura, R Nagai
    HYPERTENSION 39(1) 122-128 2002年1月  
    Various renal insults result in induction of heat shock protein (HSP) expression within the kidney. Some of the HSPs induced in that manner are postulated to have renoprotective effects via either chaperoning actions or antioxidative properties. We have previously reported that long-term angiotensin (Ang) II administration induces the expression of renal HSP32, also known as heme oxygenase-1 (HO-1). Here, we investigated the regulation of expression and localization of other HSPs, including HSP70, HSP25, and alphabeta-crystallin, in the kidney of rats undergoing long-term administration of Ana II (0.7 mg . kg(-1) . d(-1)). Immunoblot analysis demonstrated that Ang II increased renal expression of HSP70 and HSP25, as well as HO-1, but that expression of alphabeta-crystallin was unaffected by this treatment. The Ang II-induced increase in renal HSP70 and HSP25 was dependent on the angiotensin type 1 receptor activation but not on hypertension per se. Immunohistochemistry revealed that HSP70 and HSP25 were expressed in the medullar regions and in the renal arterial wall in the kidney of control rats. After Ang II infusion, signals for HSP70, HSP25, and HO-1 proteins increased in intensity in the endothelium and medial smooth muscle of the renal artery. In addition, all of these HSPs were induced in proximal renal tubular epithelial cells from the same segments, suggesting that similar mechanisms are responsible for upregulating these HSPs. Our data show that Ang II infusion induces renal HSP70 and HSP25, as well as HO-1, and that Ang II can induce expression of these HSPs in renal cells in a pressor-independent manner.
  • R Aikawa, T Nagai, M Tanaka, Y Zou, T Ishihara, H Takano, H Hasegawa, H Akazawa, M Mizukami, R Nagai, I Komuro
    Biochemical and biophysical research communications 289(4) 901-7 2001年12月14日  査読有り
    Mechanical stress induces various hypertrophic responses including activation of mitogen-activated protein kinases (MAPKs) in cardiac myocytes. Here we examined the role of the small GTP-binding proteins of Rho family and reactive oxygen species (ROS) in stretch-induced activation of p38MAPK in cardiomyocytes. Overexpression of dominant-negative mutants of Rac1 (D.N. Rac1), D.N.RhoA and D.N.Cdc42 suppressed stretch-induced activation of p38MAPK. Overexpression of constitutively active mutants of Rac1 (C.A.Rac1) and C.A.Cdc42 increased the p38MAPK activity in the absence of mechanical stress. Pretreatment with N-acetyl-L-cysteine and N-(2-mercaptopropionyl)-glycine (NAC) suppressed stretch-induced activation of p38MAPK. Mechanical stretch increased intracellular ROS generation, which was abrogated by overexpression of D.N.Rac1 and attenuated by overexpression of D.N.RhoA and D.N.Cdc42. An increase in protein synthesis evoked by mechanical stretch was suppressed by overexpression of D.N.Rac1 and pretreatment with NAC. These results suggest that mechanical stress induces cardiac hypertrophy through the Rac1-ROS-p38MAPK pathway in cardiac myocytes.
  • Y Seko, N Takahashi, H Oshima, O Shimozato, H Akiba, K Takeda, T Kobata, H Yagita, K Okumura, M Azuma, R Nagai
    JOURNAL OF PATHOLOGY 195(5) 593-603 2001年12月  
    Antigen-specific T-cells infiltrate the heart and play an important role in the myocardial damage involved in acute myocarditis and dilated cardiomyopathy. To investigate the roles of the co-stimulatory molecules CD30/CD30L, CD27/CD27L, OX40/OX40L, and 4-1BB/4-1BBL, which belong to the tumor necrosis factor (TNF) receptor/ligand superfamily, in the development of acute viral myocarditis, the expression of these molecules was first analysed in the hearts of mice with acute myocarditis induced by Coxsackievirus B3 (CVB3) in vivo. Secondly, the induction of these molecules was evaluated on cultured cardiac myocytes treated with interferon (IFN)-gamma and the interleukin (IL)-6 production by cultured cardiac myocytes was analysed by stimulation with monoclonal antibodies (MAbs) against these molecules in vitro. Thirdly, the effects of in vivo administration of anti-CD30L, anti-CD27L, anti-OX40L, or anti-4-1BBL MAb on the development of acute viral myocarditis were examined. CVB3-induced myocarditis resulted in the induction of CD30L and 4-1BBL on the surface of cardiac myocytes, confirmed by treatment with IFN-gamma in vitro. CD27L and OX40L were constitutively expressed on cardiac myocytes in vivo and in vitro. Anti-CD30L and anti4-1BBL MAbs stimulated IL-6 production by cardiac myocytes in vitro. Furthermore, in vivo anti-4-1BBL MAb treatment significantly decreased the myocardial inflammation, whereas the other MAbs did not. These findings suggest that TNF ligand superfamily co-stimulatory molecules, especially 4-1BBL, play an important role in the development of acute viral myocarditis and raise the possibility that immunotherapy with anti-4-1BBL MAb may be of benefit in acute viral myocarditis. Copyright (C) 2001 John Wiley & Sons, Ltd.
  • R H Birkhahn, T J Gaeta, D Paraschiv, J J Bove, T Suzuki, H Katoh, R Nagai
    Annals of emergency medicine 38(6) 628-32 2001年12月  査読有り
    STUDY OBJECTIVE: Serum markers of smooth muscle destruction have been shown to be elevated in ectopic pregnancy, but they remain of questionable clinical utility. Our goal was to determine the clinical utility of 3 markers of smooth muscle destruction: creatine phosphokinase (CPK), smooth muscle heavy-chain myosin (SMHC), and myoglobin. METHODS: This was a prospective cohort study, with consecutive enrollment of all women in the first trimester of pregnancy who presented to our urban emergency department with complaints of lower abdominal pain, vaginal bleeding, or both. Patients were excluded from the study if there was a history of recent surgery or major trauma. Data analysis included receiver operating characteristic (ROC) curve, 95% confidence intervals (CIs), and a regression model. RESULTS: A total of 378 patients were enrolled, with 61 patients diagnosed with an ectopic pregnancy, and 317 patients placed in the non-ectopic pregnancy group with other diagnoses. ROC curve analysis revealed an area under the curve of 0.56 (95% CI 0.51 to 0.61) for CPK, 0.63 (95% CI 0.59 to 0.68) for SMHC, and 0.58 (95% CI 0.53 to 0.63) for myoglobin. A regression model analyzing the effects of race, maternal age, estimated gestational age, and serum levels of human chorionic gonadotropin beta-subunit found no significant confounders. CONCLUSION: Although there is a statistically significant elevation in the serum levels of SMHC, the range of values seen is too large to allow SMHC to be a useful screening tool.
  • R Nagai, T Suzuki, K Aizawa, S Miyamoto, T Amaki, K Kawai-Kowase, K I Sekiguchi, M Kurabayashi
    Annals of the New York Academy of Sciences 947 56-66 2001年12月  査読有り
    The smooth muscle myosin heavy chain (MHC) gene and its isoforms are excellent molecular markers that reflect smooth muscle phenotypes. The SMemb/Nonmuscle Myosin Heavy Chain B (NMHC-B) is a distinct MHC gene expressed predominantly in phenotypically modulated SMCs (synthetic-type SMC). To dissect the molecular mechanisms governing phenotypic modulation of SMCs, we analyzed the transcriptional regulatory mechanisms underlying expression of the SMemb gene. We previously reported two transcription factors, BTEB2/IKLF and Hex, which transactivate the SMemb gene promoter based on the transient reporter transfection assays. BTEB2/IKLF is a zinc finger transcription factor, whereas Hex is a homeobox protein. BTEB2/IKLF expression in SMCs is downregulated with vascular development in vivo but upregulated in cultured SMCs and in neointima in response to vascular injury after balloon angioplasty. BTEB2/IKLF and Hex activate not only the SMemb gene but also other genes activated in synthetic SMCs including plasminogen activator inhibitor-1 (PAI-1), iNOS, PDGF-A, Egr-1, and VEGF receptors. Mitogenic stimulation activates BTEB2/IKLF gene expression through MEK1 and Egr-1. Elevation of intracellular cAMP is also important in phenotypic modulation of SMCs, because the SMemb promoter is activated under cooperatively by cAMP-response element binding protein (CREB) and Hex.
  • Y Oh-hashi, T Shindo, Y Kurihara, T Imai, Y Wang, H Morita, Y Imai, Y Kayaba, H Nishimatsu, Y Suematsu, Y Hirata, Y Yazaki, R Nagai, T Kuwaki, H Kurihara
    Circulation research 89(11) 983-90 2001年11月23日  査読有り
    alpha-Calcitonin gene-related peptide (alphaCGRP) is a pleiotropic neuropeptide implicated in a variety of physiological processes. To better understand the biological functions of alphaCGRP, we developed an alphaCGRP-null mouse model using a gene targeting approach. Recordings of mean arterial pressure (MAP) and heart rate (HR) showed that basal MAP and HR were significantly higher in both anesthetized and conscious, unrestrained alphaCGRP-null mice than in corresponding wild-type mice. The elevated MAP in alphaCGRP-null mice was shown to be the result of elevated peripheral vascular resistance by alpha-adrenergic blockade with prazosin and by transthoracic echocardiogram, which revealed no significant differences between alphaCGRP-null and wild-type mice in the stroke volume, fractional shortening, and ejection fraction. Moreover, evaluation of autonomic nervous activity by measuring HR after pretreatment of atropine and/or atenolol and by analyzing arterial baroreceptor reflexes showed sympathetic nervous activity to be significantly elevated in alphaCGRP-null mice; elevated levels of urinary catecholamine metabolites and decreased HR variability in mutant mice were also consistent with that finding. These findings suggest that alphaCGRP contributes to the regulation of cardiovascular function through inhibitory modulation of sympathetic nervous activity.
  • H Nishimatsu, Y Hirata, H Hayakawa, D Nagata, H Satonaka, E Suzuki, S Horie, T Takeuchi, N Ohta, Y Homma, S Minowada, R Nagai, K Kawabe, T Kitamura
    PEPTIDES 22(11) 1913-1918 2001年11月  
    We have reported that adrenomedullin (AM)-induced vasodilation is at least in part nitric oxide (NO)-cGMP-dependent in the rat. Although it is well known that NO is much involved in the erectile function, it is controversial as to whether AM influences the erectile function. Thus, we examined the effects of AM on intracavernous pressure (ICP) during penile erection. The left carotid artery of rats was cannulated to monitor of mean arterial pressure (MAP). Bipolar electrodes were positioned on the cavernous nerve. The right cavernous body was cannulated with a needle connected to a pressure transducer to monitor ICP. Electrical stimulation (ES) increased ICP in a voltage-dependent manner. Elevation of ICP continued during ES. The intracavernous injection of 0.5 nmol AM significantly potentiated ES-induced increases in both maximal developed ICP/MAP and area under the curve (ICP trace; AUC). Since AM slightly lowered MAP, ICP was normalized by MAP. i.v. administration of N-omega-nitro-L-arginine, a NO synthase inhibitor, markedly decreased AM/ES-induced ICP elevation. However, in the presence of E-4021, a eGMP-specific phosphodiesterase inhibitor, AM further increased both ICP/MAP and AUC. These results suggest that a NO-cGMP pathway is involved in the regulation of AM-induced rat cavernous vasorelaxation. (C) 2001 Elsevier Science Inc. All rights reserved.
  • YZ Zou, R Nagai, T Yamazaki
    FEBS LETTERS 508(1) 57-60 2001年11月  
    Urotensin II (UII), a cyclic neuropeptide, functions not only in the central nervous system but also in non-neural systems including cardiovascular systems. In the present study we examined whether UII regulates hypertrophy in cardiomyocytes. The exposure of cultured cardiomyocytes from neonatal rats to UII dose-dependently activated extracellular signal-regulated kinases (ERKs), important molecules in the development of cardiac hypertrophy. ERK activation by UII at 100 nM peaked at 8 min after stimulation. UII markedly induced expression of specific genes encoding atrial natriuretic peptide and brain natriuretic peptide, and significantly increased amino acid incorporation into proteins. Incubation of cardiomyocytes with UII increased cell size and myofibril organisation. UII, then, might participate in cardiomyocyte hypertrophy. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.
  • M Sata, S Sugiura, M Yoshizumi, Y Ouchi, Y Hirata, R Nagai
    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 21(11) 1733-1737 2001年11月  
    Vascular smooth muscle cell (VSMC) apoptosis has been demonstrated in vascular lesions, such as atherosclerotic and postangioplasty restenotic lesions. Balloon injury also induces VSMC apoptosis. Fas is a death factor that mediates apoptosis when it is activated by its ligand, FasL. Fas-mediated apoptosis was found to be implicated in the pathogenesis of vascular diseases in which Fas/FasL expression was detected. We investigated whether the Fas/FasL interaction mediated acute and chronic VSMC apoptosis and lesion formation in a vascular injury model that may resemble balloon angioplasty. A large spring wire was inserted into the femoral artery of C3H/HeJ (wild-type), C3H-gld (Fas ligand-/-), and C3H-lpr (Fas-/-) mice. The wire was left in place for 1 minute to denude and expand the artery. Massive apoptosis was observed in medial VSMCs from 1 to 7 hours later. There was no difference in the number of apoptotic cells among the 3 groups of mice 4 hours after injury. At 4 weeks, the injured arteries presented signs of concentric neointimal hyperplasia composed exclusively of VSMCs. There was no difference in the degree of neointima hyperplasia (intima/media ratios were as follows: wild type 1.4 +/- 0.3, gld 1.0 +/- 0.2, and lpr 1.3 +/- 0.2) or in the number of apoptotic nuclei among the 3 groups. These findings suggest the existence of other signaling pathways for acute and chronic VSMC apoptosis, at least that induced by mechanical vascular injury.
  • T Yamagishi, Y Saito, T Nakamura, S Takeda, H Kanai, H Sumino, M Kuro-o, Y Nabeshima, M Kurabayashi, R Nagai
    Hypertension research : official journal of the Japanese Society of Hypertension 24(6) 705-9 2001年11月  
    Targeted disruption of the klotho gene induces multiple phenotypes characteristic of human aging, including arteriosclerosis, pulmonary emphysema and osteoporosis. Moreover, we previously observed that insufficient klotho expression in mice leads to endothelial dysfunction. In the present study, we used Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which exhibit hypertension, obesity, severe hyperglycemia and hypertriglyceridemia, and are thus considered an animal model of atherogenic disease, to test the effects of oral administration of troglitazone (200 mg/kg) on renal klotho mRNA expression and endothelial function. Systolic blood pressure, body weight, plasma glucose and triglyceride levels were all significantly higher in 30-week-old OLETF rats than in controls (LETO; Long-Evans Tokushima Otsuka) (p<0.05, n=7). In addition, endothelium-dependent relaxation of the aorta in response to 10(-5) M acetylcholine was significantly attenuated in OLETF rats (p<0.05, n=7), as was renal expression of klotho mRNA. Administration of troglitazone for 10 weeks significantly reduced systolic blood pressure, plasma glucose and triglyceride levels in OLETF rats, while augmenting endothelium-dependent aortic relaxation and renal klotho mRNA expression. These findings suggest that troglitazone protects the vascular endothelium against damage caused by the presence of multiple atherogenic factors.
  • 菊地 裕絵, 飯田 陽子, 村川 裕二, 森田 敏宏, 小早川 直, 宇野 漢成, 中村 文隆, 竹中 克, 大野 実, 平田 恭信, 永井 良三, 大塚 俊哉, 小塚 裕, 高本 眞一
    Japanese circulation journal 65 2001年10月20日  
  • 水野 由子, 小田島 慎也, 松本 晃裕, 西村 敬史, 園田 誠, 宇野 漢成, 中村 文隆, 杉浦 清了, 鈴木 順一, 大野 実, 竹中 克, 平田 恭信, 永井 良三
    Japanese circulation journal 65 2001年10月20日  
  • K Tobe, R Suzuki, M Aoyama, T Yamauchi, J Kamon, N Kubota, Y Terauchi, J Matsui, Y Akanuma, S Kimura, J Tanaka, M Abe, J Ohsumi, R Nagai, T Kadowaki
    The Journal of biological chemistry 276(42) 38337-40 2001年10月19日  査読有り
    Insulin receptor substrate (IRS)-2(-/-) mice develop diabetes because of insulin resistance in the liver and failure to undergo beta-cell hyperplasia. Here we show by DNA chip microarray analysis that expression of the sterol regulatory element-binding protein (SREBP)-1 gene, a downstream target of insulin, was paradoxically increased in 16-week-old IRS-2(-/-) mouse liver, where insulin-mediated intracellular signaling events were substantially attenuated. The expression of SREBP-1 downstream genes, such as the spot 14, ATP citrate-lyase, and fatty acid synthase genes, was also increased. Increased liver triglyceride content in IRS-2(-/-) mice assures the physiological importance of SREBP-1 gene induction. IRS-2(-/-) mice showed leptin resistance; low dose leptin administration, enough to reduce food intake and body weight in wild-type mice, failed to do so in IRS-2(-/-) mice. Interestingly, high dose leptin administration reduced SREBP-1 expression in IRS-2(-/-) mouse liver. Thus, IRS-2 gene disruption results in leptin resistance, causing an SREBP-1 gene induction, obesity, fatty liver, and diabetes.

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