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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

 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  
もっとみる

MISC

 1913
  • Y Seta, T Kanda, T Yokoyama, M Arai, K Sekiguchi, T Tanaka, I Kobayashi, M Kurabayashi, R Nagai
    Japanese heart journal 41(1) 79-85 2000年1月  査読有り
    Endothelin-1 (ET-1) is a potent vasoconstrictor. This peptide exerts numerous effects on the heart, including regulation of cardiomyocyte growth during hypertrophy. The effects of the structurally novel, nonpeptide, ET-1-selective, competitive antagonist (ETA) 97-139 were investigated in mice with congestive heart failure (CHF) and myocardial hypertrophy. Morphological and microscopical analyses were conducted on day 56 after viral inoculation following 28 day treatment with 99-139. Eight week-old DBA2 mice were intraperitoneally inoculated with encephalomyocarditis virus at a dose of 500 pfu/mouse. The 30 mice were divided into two groups--an ETA treated group and an untreated group. Heart weight (HW) in the infected group was significantly (p < 0.05) increased compared to that in the uninfected group. HW and the HW/body weight (BW) ratio were significantly (p < 0.05) reduced in the ETA treated group compared with the untreated group (HW; 127.7 +/- 6.2 mg vs 144.3 +/- 4.2 mg, HW/BW; 4.9 +/- 0.9 x 10(-3) vs 5.4 +/- 0.5 x 10(-3)). Myofiber diameter in the ETA treated group was significantly reduced compared with the untreated group (12.1 +/- 1.5 microm vs 14.3 +/- 1.9 microm). These results suggest the ET-1 receptor antagonist 97-139 has an effect on the reduction of cardiac mass and myofiber hypertrophy, and that 97-139 may be a useful agent for CHF due to viral myocarditis.
  • K Kaneko, T Kanda, A Hasegawa, T Suzuki, I Kobayashi, R Nagai
    Japanese heart journal 41(1) 41-7 2000年1月  査読有り
    The prognosis of patients with lymphocytic myocarditis (LM) is poor with the combined endpoint of death or transplant in the Myocarditis Treatment trial being 56% at 5 years. Physicians often have difficulty determining the prognosis in an individual patient. Patients with LM may have ongoing myocardial inflammation. We evaluated the ability of a serum marker of inflammation to predict prognosis in patients with LM. Serum concentrations of C-reactive protein (CRP) were measured in patients with LM. Thiry-one patients with clinical and histologic evidence of LM were evaluated. Patients with coronary artery disease, and idiopathic dilated and secondary cardiomyopathies were excluded. Overall mortality and morbidity from congestive heart failure was assessed at 28 days. The mean plasma CRP concentrations in the five patients who died within the 28-day follow-up period were significantly higher than in those patients who survived (17.4 +/- 5.6 vs 5.9 +/- 3.3 mg/ml, p < 0.05). The CRP concentration was positively correlated with plasma levels of lactic dehydrogenase and the New York Heart Association functional class. Routine measurement of CRP may be a useful tool for determining the prognosis in patients with LM.
  • Y Seko, H Nishimura, N Takahashi, T Ashida, R Nagai
    JAPANESE HEART JOURNAL 41(1) 27-32 2000年1月  
    We have previously reported that pulsatile mechanical stretch in vitro induced rapid secretion of vascular endothelial growth factor (VEGF) by cultured cardiac myocytes and that the stretch-induced secretion of VEGF was mainly mediated by secretion of transforming growth factor (TGF)-beta 1 by cardiac myocytes in an autocrine fashion. To investigate whether tachycardia-induced mechanical overload increases serum levels of VEGF and TGF-beta 1, we investigated the serum levels of VEGF and TGF-beta 1 in patients with atrial fibrillation undergoing defibrillation therapy. The serum VEGF level before defibrillation was significantly increased in 13 out of 20 patients (89.48 +/- 16.09 pg / ml [mean +/- SE]), After defibrillation, the serum VEGF level in these 13 patients significantly (p=0.019) decreased (65.04 +/- 16.61 pg/ml [mean +/- SE]), although it increased slightly in one patient. The serum TGF-beta 1 level before defibrillation therapy (13.01 +/- 1.97 pg / mi [mean +/- SE]) in these 12 patients also decreased after defibrillation therapy (11.47 +/- 2.06 pg / mi [mean +/- SE]). The changes in serum VEGF level significantly correlated with those in the serum TOE-beta 1 level in these 12 patients (r = 0.73, p &lt; 0.05, n = 12). Our data suggest that tachyarrhythmia-induced mechanical overload can increase the serum VEGF level, which can be a useful clinical marker for relative myocardial oxygen shortage in such patients.
  • Jpn J Pharmacol 82(Suppl (]G0001[)) 25 2000年  
  • Y Terauchi, N Kubota, H Tamemoto, H Sakura, R Nagai, Y Akanuma, S Kimura, T Kadowaki
    Diabetes 49(1) 82-6 2000年1月  査読有り
    Low birth weight has been reported to be associated with impaired insulin secretion and insulin resistance. It has been proposed that this association results from fetal programming in response to the intrauterine environment (the thrifty phenotype hypothesis). To elucidate the relationship between birth weight and genetically determined defects in insulin secretion, we measured the birth weights of neonates derived from crosses of male pancreatic beta-cell type glucokinase knockout (Gck+/-) mice and female wild-type (WT) or Gck+/- mice. In 135 offspring, birth weights were lower in the presence of a fetal heterozygous mutation and higher in the presence of a maternal heterozygous mutation. Moreover, Gck-/- neonates had significantly smaller birth weights than WT or Gck+/- neonates (means +/- SE 1.49+/-0.03 [n = 30] vs. 1.63+/-0.03 [n = 30] or 1.63+/-0.02 [n = 50] g, respectively; P<0.01). Thus, Gck mutations in beta-cells may impair insulin response to glucose and alter intrauterine growth as well as glucose metabolism after birth. This study has confirmed the results of a previous report that human subjects carrying mutations in Gck had reduced birth weights and has provided direct evidence for a link between insulin and fetal growth. Moreover, birth weights were reduced in insulin receptor substrate-1 knockout mice despite normal insulin levels. Taken together, these results suggest that a genetically programmed insulin effect during embryogenesis determines fetal growth and provides a possible molecular link between birth weight and susceptibility to type 2 diabetes.
  • H Sato, T Iwasaki, T Toyama, Y Kaneko, T Inoue, K Endo, R Nagai
    CHEST 117(1) 65-72 2000年1月  
    Study objectives: Clinical studies comparing fatty acid and glucose metabolism in relation to functional recovery of ischemic myocardium after coronary revascularization are scarce. This study evaluated the recovery of regional and global left ventricular function after coronary revascularization in relation to uptake patterns of beta-methyl-iodophenyl-pentadecanoic acid (BMIPP) and fluorodeoxyglucose (FDG) in patients with ischemic myocardial dysfunction. Methods: Patients with ischemic regional wall motion abnormality underwent baseline viability imaging with F-18-FDG, I-123-BMIPP, and Tc-99m- methoxyisobutylisonitrile, and the regions with evidence for maintained tissue viability were revascularized. Mismatch of uptake score between two different single-photon emission CT (SPECT) images in the same myocardial region was graded as low or high mismatch. Regional and global left ventricular functional changes after revascularization were analyzed in relation to mismatch severity and difference of total uptake score in each SPECT image pair. A total of 33 vessels in 30 patients related to the as)nergic regions were revascuIarized, and a total of 100 myocardial segments perfused by the revascularized vessels were analyzed. Results: Segments shoning high metabolic mismatch (FDG/BMIPP) had lowest regional wall motion score at baseline, representing the most severely impaired ischemic myocardium, and had highest improvement in regional wall motion score after revascularization. Difference of total uptake score between FDG and BMIPP showed a significant positive correlation with difference of ejection fraction between pre- and postrevascularization (r = 0.774, p &lt; 0.0001), Conclusions: Combined metabolic SPECT imaging with FDG and BMIPP has the potential to identify severely impaired ischemic myocardium leading to more efficient therapeutic management of patients with coronary artery disease.
  • K Aizawa, T Nakamura, Y Ohyama, Y Saito, J Hoshino, T Kanda, H Sumino, R Nagai
    NEPHRON 84(1) 67-70 2000年1月  
    Epidermal nevus syndrome is an unusual neurocutaneous disorder in which epidermal nevi are associated with abnormalities of the skeleton and central nervous system, including the eyes and somtimes the cardiovascular system. We treated a patient in whom the latter included renal artery stenosis. An 18-year-old man with epidermal nevi was diagnosed as having the syndrome based on the additional presence of scoliosis, an arachnoid cyst in the middle cranial fossa, and microphthalmos. Hypertension was diagnosed when the patient was 15 years old. The plasma renin activity (9.7 ng/ml/h) was elevated. Right renal artery stenosis was demonstrated by angiography, and the abdominal aorta was narrowed distal to the ostium of the superior mesenteric artery. The plasma renin activity in the right renal vein (16 ng/ ml/h) was higher than contralaterally (10 ng/ml/h), Several cardiovascular manifestations have been reported as a complication of epidermal nevus syndrome. Hypertension in an individual with epidermal nevi and congenital anomalies should prompt a search for a vascular anomaly. Copyright (C) 2000 S. Karger AG. Basel.
  • T Suzuki, A Kimura, R Nagai, M Horikoshi
    Genes to cells : devoted to molecular & cellular mechanisms 5(1) 29-41 2000年1月  査読有り
    BACKGROUND: The coactivator p300 acts as a transcriptional adaptor for many DNA-binding activators. The finding that p300 possesses intrinsic acetyltransferase activity which, by chemically modifying histone tails affects the nucleosomal environment and transcription, has greatly advanced our understanding of its function. Subsequent recent studies have shown that non-histone proteins are also acetylated. However, one central question which has remained unanswered is how the coactivator/acetyltransferase interacts with DNA-binding activators to modulate their actions. RESULTS: Here we have demonstrated physical and functional interaction between the acetyltransferase region of p300 and the DNA-binding domain (DBD) of the transcription factor Sp1. This interaction stimulates DNA binding by the DBD of Sp1, which is mediated primarily by physical interaction rather than acetylation, despite acetylation of the DBD of Sp1 by the acetyltransferase region of p300. Furthermore, DNA binding by the DBD of Sp1 inhibits both its association and acetylation by the acetyltransferase region of p300. CONCLUSIONS: These findings suggest a new role for p300 in regulating promoter access by DNA-binding activators through multiple regulatory interactions.
  • M Arai, A Yoguchi, T Takizawa, T Yokoyama, T Kanda, M Kurabayashi, R Nagai
    CIRCULATION RESEARCH 86(1) 8-14 2000年1月  
    Doxorubicin (DOX)-induced cardiomyopathy has been found to be associated with impaired Ca2+ handling in the sarcoplasmic reticulum (SR), leading to reduced cardiac function. We have recently demonstrated that expression of mRNA encoding sarco(endo)plasmic reticulum Ca2+-ATPase 2 (SERCA2), a major Ca2+ transport protein in SR, is markedly decreased in DOX-treated hearts. To extend this observation, we have dissected the molecular mechanisms by which DOX downregulates SERCA2 gene transcription. Using cultured rat neonatal cardiac myocytes, we found that the antioxidant N-acetylcysteine blocked the DOX-induced decrease in SERCA2 mRNA levels, as well as the DOX-induced increase in H2O2 concentration; thus, H2O2 is an intracellular mediator of DOX activity. Using a luciferase reporter assay, we found that the sequence from -284 to -72 bp in the 5' flanking region of the SERCA2 gene has a DOX-responsive element. Although several transcription factors have putative binding motifs in this region of the SERCA2 gene, only the expression of Egr-1 mRNA and the binding of Egr-1 protein to the 5' regulatory sequence of SERCA2 gene increased markedly after DOX administration. We also found that overexpression of Egr-1 was associated with a significant reduction in SERCA2 gene transcription. In addition, Egr-1 antisense oligonucleotides blocked the DOX-induced reduction in SERCA2 mRNA, suggesting that Egr-1 is a transcriptional inhibitor of the SERCA2 gene in DOX-induced cardiomyopathy. We observed activation of 3 mitogen-activated protein kinases (MAPKs), p44/42 MAPK, p38 MAPK, and stress-activated MAPK/Jun N-terminal kinase, by DOX, but only a specific inhibitor of the p44/42 MAPK kinase suppressed the effects of DOX on Egr-1 and SERCA2 mRNA expression. These findings indicate that reactive oxygen intermediates, the transcription factor Egr-1, and p44/42 MAPK are critical elements in the transcriptional regulation of the SERCA2 gene in response to DOX.
  • T Suga, M Kurabayashi, Y Sando, Y Ohyama, T Maeno, Y Maeno, H Aizawa, Y Matsumura, T Kuwaki, M Kuro-o, Y Nabeshima, R Nagai
    AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 22(1) 26-33 2000年1月  
    Homozygous mutant klotho (KL-/-) mice exhibit multiple phenotypes resembling human aging, In the present study, we focused on examining the pathology of the lungs of klotho mice and found that it closely resembled pulmonary emphysema in humans both histologically and functionally. Histology of the lung of KL-/- mice was indistinguishable from those of wild-type littermates up to 2 wk of age. The first histologic changes appeared at 4 wk of age, showing enlargement of the air spaces accompanied by destruction of the alveolar walls, and progressed gradually with age. In addition to these changes, we observed calcium deposits in type I collagen fibers in alveolar septa and degeneration of type II pneumocytes in 8- to 10-wk-old KL-/- mice. Pulmonary function tests revealed prolonged expiration time in KL-/- mice, which is comparable with the pathophysiology of pulmonary emphysema. The expression level of messenger RNA for type IV collagen, surfactant protein-A and mitochondrial ger RNA for type IV collagen, surfactant protein-A and mitochondrial beta-adenosine triphosphatase was significantly increased in KL-/- mice, which may represent a compensatory response to alveolar destruction. Additionally, the heterozygous mutant klotho mice also developed pulmonary emphysema late in life, around 120 wk of age. These findings indicate that klotho gene expression is essential to maintaining pulmonary integrity during postnatal life. The klotho mutant mouse is a useful laboratory animal model for examining the relationship between aging and pulmonary emphysema.
  • H Sumino, T Nakamura, S Ichikawa, T Kanda, T Sakamaki, K Sato, I Kobayashi, R Nagai
    Atherosclerosis 148(1) 189-95 2000年1月  査読有り
    The administration of hormone replacement therapy (HRT) to postmenopausal women (PMW) reportedly has beneficial effects on their levels of lipid and lipoproteins. Estrogen retards the development of atherosclerosis induced by a high-fat diet in animals. Although vascular endothelial growth factor (VEGF) may be involved in the development of atherosclerosis in humans, there is no information on effect of estrogen administration on VEGF level and lipid metabolism. We evaluated 64 healthy normotensive or hypertensive PMW before and during the administration of HRT (0.625 mg conjugated equine estrogen combined with 2.5 mg medroxyprogesterone acetate orally) daily for 6 months. All hypertensive PMW were well-controlled on antihypertensive drug therapy. According to their total cholesterol level at baseline, we divided the PMW with HRT (n=54) into a normocholesterolemic group (NC, total cholesterol <220 mg/dl, n=35) and a hypercholesterolemic group (HC, total cholesterol >/=220 mg/dl, n=19). We evaluated the serum levels of VEGF at baseline, and again at 3 and 6 months after starting HRT. HRT significantly (P<0.01) reduced the mean VEGF level from 31.5+/-4.3 pg/ml at baseline to 18.2+/-2.3 pg/ml after 6 months in the NC group. However, the VEGF levels in the HC group and the control group exhibited no significant change at either 3 or 6 months after starting HRT. In summary, HRT, using a combination of conjugated equine estrogen and medroxyprogesterone acetate, reduced the level of VEGF in normocholesterolemic PMW more effectively than in those with hypercholesterolemia.
  • M Shimoyama, D Hayashi, E Takimoto, Y Zou, T Oka, H Uozumi, S Kudoh, F Shibasaki, Y Yazaki, R Nagai, I Komuro
    Circulation 100(24) 2449-54 1999年12月14日  査読有り
    BACKGROUND: Cardiac hypertrophy is a fundamental adaptive response to hemodynamic overload; how mechanical load induces cardiac hypertrophy, however, remains elusive. It was recently reported that activation of a calcium-dependent phosphatase, calcineurin, induces cardiac hypertrophy. In the present study, we examined whether calcineurin plays a critical role in pressure overload-induced cardiac hypertrophy. METHODS AND RESULTS: Pressure overload produced by constriction of the abdominal aorta increased the activity of calcineurin in the rat heart and induced cardiac hypertrophy, including reprogramming of gene expression. Treatment of rats with a calcineurin inhibitor, FK506, inhibited the activation of calcineurin and prevented the pressure overload-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Load-induced expression of immediate-early-response genes and fetal genes was also suppressed by the FK506 treatment. CONCLUSIONS: The present results suggest that the calcineurin signaling pathway plays a pivotal role in load-induced cardiac hypertrophy and may pave the way for a novel pharmacological approach to prevent cardiac hypertrophy.
  • 永井 良三, 森田 啓行, 山崎 力, 安喰 恒輔, 村川 裕二, 林 同文
    内科 84(6) 1002-1012 1999年12月  
  • Y Hamada, S Ishikawa, T Kanda, S Imai, R Nagai, K Matsui, N Ohashi, Y Morishita
    International angiology : a journal of the International Union of Angiology 18(4) 320-6 1999年12月  査読有り
    PURPOSE: This study was designed to investigate the effect of a newly synthesised sodium/hydrogen ion exchange inhibitor, SM-20550, on ischaemia-reperfusion induced injury in a rat hind limb model. METHODS: In order to induce ischaemia of the hind limbs, the abdominal aorta just distal to the renal arteries and the bilateral femoral arteries were clamped. Nineteen rats were divided into three groups. In the sham group (n=5), the vessels were only dissected and a vehicle solution was administered. In the control group (n=7), the vessels were clamped for five hours, and a vehicle solution was administered 10 minutes prior to clamping and continued for five hours after reperfusion. In the SM group (n=7), clamping was maintained for five hours with a bolus injection of SM-20550 and continuous infusion of the solution for five hours after reperfusion. Water content of the left gastrocnemius muscle was calculated. The right gastrocnemius was fixed in 10% formalin. A transverse thin section was stained with antimyoglobin antibody. Stained cells of the right gastrocnemius were counted and the myoglobin staining index was calculated. RESULTS: Water content was significantly (p<0.002) lower in the SM group than in the control group. The myoglobin staining index was significantly (p<0.01) higher in the SM group than in the control group. There was no significant difference between the control and the SM groups in creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH). CONCLUSIONS: Our results indicate that the sodium/hydrogen ion exchange inhibitor, SM-20550, ameliorates oedema formation and ischaemia-reperfusion induced injury of the skeletal muscle.
  • T Takizawa, M Arai, A Yoguchi, K Tomaru, M Kurabayashi, R Nagai
    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 31(12) 2167-2174 1999年12月  
    The sarcoplasmic reticulum Ca2+-ATPase (SERCA2) controls the myocardial relaxation process, Under pressure-overload, the expression of its mRNA decreases, thus controlling cardiac function to conform to the load. However, it is not known whether this decreased expression is caused by a decrease in the transcription of the SERCA2 gene. The object of this study was to determine the transcription control mechanism of the SERCA2 gene under pressure-overload in vivo, and to identify the pressure-overload-sensitive regions of the SERCA2 gene. Ten micrograms of a plasmid, containing the 5' upstream (-1810 bp to + 350 bp) region of the SERCA2 gene and a luciferase reporter gene, were introduced into adult rat myocardium by in vivo direct gene transfer, and the luciferase activity was measured 5 days later. The transcriptional activity under pressure-overload decreased to 27 +/- 17% of the control. Based on this result, we concluded that the decreased mRNA expression of SERCA2 in pressure-overload cardiac hypertrophy is due to decreased gene transcription. In addition, various deletion fragments of the SERCA2 promoter region were produced, and tested for luciferase production under pressure-overload. Our data suggest that a transcription activation site is present between -685 and -284 bp, and two transcription inhibition sites are present between -1810 to -1110 bp and -284 to -72 bp, These map be the pressure-sensitive regions of the SERCA2 gene of in vivo hypertrophied myocardium under pressure-overload. (C) 1999 Academic Press.
  • N Ishizaka, A Nakao, N Ohishi, M Suzuki, T Aizawa, J Taguchi, R Nagai, T Shimizu, M Ohno
    FEBS LETTERS 463(1-2) 155-159 1999年12月  
    Leukotriene A(4) (LTA(4)) hydrolase is essential for the conversion of LTA(4) to LTB4, an inflammatory lipid mediator, We investigated whether LTA(4) hydrolase was regulated in the heart by angiotensin II (ang IT) infusion. Continuous ang II infusion via an osmotic minipump for up to 7 days upregulated mRNA and protein levels of LTA(4) hydrolase (similar to 3.5-fold of control) in the heart in a presser-dependent manner. Immunohistochemistry demonstrated intense LTA(4) hydrolase staining in the myofibroblast as well as migrated monocytes/macrophages. These data suggest that the cardiac LTA(4) hydrolase-LTB4 system plays a positive role in the promotion of cardiac inflammation in hypertension. (C) 1999 Federation of European Biochemical Societies.
  • T Nagase, H Kurihara, Y Kurihara, T Aoki-Nagase, R Nagai, Y Ouchi
    JOURNAL OF APPLIED PHYSIOLOGY 87(6) 2020-2024 1999年12月  
    Endothelin (ET)-1 has been shown to have various pathophysiological roles in the lung. Recently, it has been reported that ET-1 and a gene encoding ET-1 (Edn1) might be involved in airway hyperresponsiveness, which isa major feature of bronchial asthma. Meanwhile, it remains unclear whether ET-1 might be involved in airway remodeling in vivo. In the present study, we hypothesized whether ET-1 might play a role in airway remodeling,leading to altered responsiveness. To test this hypothesis, we investigated airway function in vivo and airway wall structure in Edn1(+/-) heterozygous knockout mice, which genetically produce lower levels of ET-1, and Edn1(+/+) mild-type mice. In the physiological study, enhanced responses in lung elastance and resistance to methacholine administration were observed in Edn1(+/-) mice, whereas there was no difference in serotonin responsiveness. In the morphometric study, there were no differences in either lamina propria or airway smooth muscle thickness between Edn1(+/-) mice and Edn1(+/+) mice; These findings suggest that ET-1 gene disruption is involved in methacholine pulmonary hyperresponsiveness via functional mechanism, but not airway remodeling, in mice. The ET-1 knockout mice may provide appropriate models to study diseases related to ET-1 metabolism.
  • N Yahagi, H Shimano, AH Hasty, M Amemiya-Kudo, H Okazaki, Y Tamura, Y Iizuka, F Shionoiri, K Ohashi, J Osuga, K Harada, T Gotoda, R Nagai, S Ishibashi, N Yamada
    JOURNAL OF BIOLOGICAL CHEMISTRY 274(50) 35840-35844 1999年12月  
    Dietary polyunsaturated fatty acids (PUFA) are negative regulators of hepatic lipogenesis that exert their effects primarily at the level of transcription. Sterol regulatory element-binding proteins (SREBPs) are transcription factors responsible for the regulation of cho lesterol, fatty acid, and triglyceride synthesis. In particular, SREBP-1 is known to play a crucial role in the regulation of lipogenic gene expression in the liver. To explore the possible involvement of SREBP-1 in the suppression of hepatic lipogenesis by PUFA, we challenged wild-type mice and transgenic mice overexpressing a mature form of SREBP-1 in the liver with dietary PUFA. In the liver of wild-type mice, dietary PUFA drastically decreased the mature, cleaved form of SREBP-1 protein in the nucleus, whereas the precursor, uncleaved form in the membranes was not suppressed. The decreases in mature SREBP-1 paralleled those in mRNAs for Lipogenic enzymes such as fatty acid synthase and acetyl-CoA carboxylase. In the transgenic mice, dietary PUFA did not reduce the amount of transgenic SREBP-1 protein, excluding the possibility that PUFA accelerated the degradation of mature SREBP-1. The resulting sustained expression of mature SREBP-1 almost completely canceled the suppression of lipogenic gene expression by PUFA in the SREBP-1 transgenic mice. These results demonstrate that the suppressive effect of PUFA on Lipogenic enzyme genes in the liver is caused by a decrease in the mature form of SREBP-1 protein, which is presumably due to the reduced cleavage of SREBP-1 precursor protein.
  • W Zhu, Y Zou, R Aikawa, K Harada, S Kudoh, H Uozumi, D Hayashi, Y Gu, T Yamazaki, R Nagai, Y Yazaki, I Komuro
    Circulation 100(20) 2100-7 1999年11月16日  査読有り
    BACKGROUND: Although anthracyclines, such as daunomycin (DM) and adriamycin, are potent chemotherapeutic agents, they have serious adverse effects, including cardiac toxicity. In the present study, we investigated the molecular mechanisms of DM-induced cardiomyocyte impairment. METHODS AND RESULTS: When cultured cardiac myocytes of neonatal rats were exposed to 1 micromol/L DM for 24 hours, many cells became positive for TUNEL staining, with morphological changes characteristic of apoptosis. Fragmentation of DNA into oligonucleosome-size fragments was recognized by agarose gel electrophoresis in DM-treated myocytes. DM activated 3 members of the mitogen-activated protein kinase (MAPK) family dose-dependently, such as extracellular signal-regulated protein kinases (ERKs), c-Jun NH(2)-terminal kinases, and p38 MAPK in cardiac myocytes. Oxyradical scavengers or Ca(2+) chelators inhibited DM-induced activation of ERKs and p38 MAPK. DM-induced activation of ERKs was also inhibited by overexpression of dominant negative mutants of Ras (D.N.Ras), and the p38 MAPK activation was attenuated by D.N.Rho. The number of DM-induced apoptotic cells was markedly increased when the ERK signaling pathway was selectively blocked by a specific MAPK/ERK kinase inhibitor, PD98059, whereas pretreatment with a specific inhibitor of p38 MAPK, SB203580, significantly reduced the amount of apoptosis. CONCLUSIONS: These results suggest that DM activates MAPKs through reactive oxygen species and Ca(2+) and that the MAPK family plays important roles in DM-induced apoptosis in cardiac myocytes. ERKs protect cardiomyocytes from apoptosis, whereas p38 MAPK is involved in the induction of cardiomyocyte apoptosis.
  • 中島 忠, 永井 良三
    遺伝子医学 3(4) 672-681 1999年11月  
  • Y Oyama, M Kurabayashi, N Akuzawa, S Takeda, R Nagai
    CIRCULATION 100(18) 703-703 1999年11月  
  • H Kanai, M Kurabayashi, T Tanaka, Y Aihara, SI Takeda, M Kawabata, K Miyazono, R Nagai
    CIRCULATION 100(18) 615-615 1999年11月  
  • A Watanabe, M Kurabayashi, K Sekiguchi, T Uchiyama, R Nagai
    CIRCULATION 100(18) 703-703 1999年11月  
  • KK Kowase, M Kurabayashi, H Sakamoto, Y Ohyama, R Nagai
    CIRCULATION 100(18) 743-743 1999年11月  
  • Y Saito, T Nakamura, Y Ohyama, H Alzawa, Y Matsumura, H Masuda, M Kura-o, YI Nabeshima, R Nagai
    CIRCULATION 100(18) 829-829 1999年11月  
  • T Nakajima, T Furukawa, Y Hirano, T Tanaka, H Sakurada, T Takahashi, R Nagai, T Itoh, Y Katayama, Y Nakamura, M Hiraoka
    Cardiovascular research 44(2) 283-93 1999年11月  査読有り
    OBJECTIVE: Recently, a novel missense mutation (R534C) in the S4 region of human ether-a-go-go-related gene (HERG) was identified in one Japanese LQT2 family. The S4 region presumably functions as a voltage sensor. However, it has not yet been addressed whether the S4 region of HERG indeed functions as a voltage sensor, and whether these residues play any role in abnormal channel function in cardiac repolarization. METHODS: We characterized the electrophysiological properties of the R534C mutation using the heterologous expression system in Xenopus oocytes. Whole cell currents were recorded in oocytes injected with wild-type cRNA, R534C cRNA, or a combination of both. RESULTS: Clinical features--QTc intervals of all affected patients with R534C mutation in HERG are prolonged ranging from 460 to 680 ms (averaged QTc interval > 540 ms). One member of this family had experienced sudden cardiac arrest, and other suffered from recurrent palpitation. Electrophysiology--Oocytes injected with R534C cRNA did express functional channels with altered channel gating. Kinetic analyses revealed that the R534C mutation shifted the voltage-dependence of HERG channel activation to a negative direction, accelerated activation and deactivation time course, and reduced steady-state inactivation. Quantitative analyses revealed that this mutation did not cause apparent dominant-negative suppression. Computer simulation--Incorporating the kinetic alterations of R534C, however, did not reproduce prolonged action potential duration (APD). CONCLUSIONS: The data revealed that arginine at position 534 in the S4 region of HERG is indeed involved in voltage-dependence of channel activation as a voltage sensor. Our examination indicated that HERG current suppression in R534C mutation was the least severe among other mutations that have been electrophysiologically examined, while affected patients did show significant QT prolongation. This suggest that another unidentified factor(s) that prolong APD might be present.
  • I Shiojima, M Aikawa, J Suzuki, Y Yazaki, R Nagai
    Japanese heart journal 40(6) 803-18 1999年11月  査読有り
    Left ventricular hypertrophy (LVH) is a secondary adaptation to increased external load. Various qualitative and quantitative changes in myocytes and extracellular components occur during the development of LVH. It has recently been demonstrated that alpha-smooth muscle actin (alpha-SMA)-expressing myofibroblasts appear in the interstitium of the heart subjected to increased workload suggesting that cardiac fibroblasts as well as myocytes alter their phenotype in response to pressure overload. In the present study, to explore the load-induced response and phenotypic modulation of cardiac fibroblasts, the localization of embryonic smooth muscle myosin heavy chain (SMemb) and alpha-SMA in thoracic aorta-constricted rat hearts was investigated by immunohistochemistry, and the morphology of the SMemb-expressing cells was examined by electron microscopy. In addition, to clarify the mechanisms by which SMemb is induced in pressure-overloaded hearts, mRNA expression of SMemb in aorta-constricted rat hearts and in transforming growth factor-beta1 (TGF-beta1)-treated or mechanically-stretched cultured cardiac fibroblasts was investigated. Enhanced staining of SMemb and alpha-SMA was detected in the interstitial spindle-shaped cells in the fibrotic lesions of the pressure-overloaded left ventricles by immunohistochemistry. These cells were demonstrated by electron microscopy to have features specific for activated fibroblasts such as serrated nuclei or prominent rough endoplasmic reticulum. These cells also had characteristic features of myofibroblasts, i.e. irregularly arranged actin filaments and scattered dense bodies. Northern blot analysis revealed increased mRNA levels of SMemb both in aorta-constricted rat hearts and in cultured cardiac fibroblasts stimulated by TGF-beta1 or by mechanical stretch. These results suggest that SMemb may be a molecular marker both for the detection of activated cardiac fibroblasts that may play important roles in the remodeling of pressure-overloaded cardiac interstitium, and for the identification of the regu latory mechanisms that control the phenotypic modulation of cardiac fibroblasts in response to pressure overload.
  • K Sekiguchi, T Yokoyama, M Kurabayashi, F Okajima, R Nagai
    CIRCULATION RESEARCH 85(11) 1000-1008 1999年11月  
    The sphingolipid metabolites, sphingosine (SPH), SPH 1-phosphate (S1P), and sphingosylphosphorylcholine (SPC), can act as intracellular as well as extracellular signaling molecules, These compounds have been implicated in the regulation of cell growth, differentiation, and programmed cell death in nonmyocytes, but the effects of sphingolipid metabolites in cardiac myocytes are not known. Cultured neonatal rat cardiac myocytes were stimulated with SPH (I to 10 mu mol/L), S1P (1 to 10 mu mol/L), or SPC (0.1 to 10 mu mol/L) for 24 hours to determine the effects of sphingolipid metabolites on the rates of protein synthesis, and degradation. Stimulation with SPC led to an increase in the total amount of protein, an accelerated rate of total protein synthesis, and a decrease in protein degradation in a dose-dependent manner. However, SIP had little effect and SPH had no effect on total protein synthesis. In addition, stimulation with SPC led to a 1.4-fold increase in myocardial cell size and enhanced atrial natriuretic factor gene expression. Pretreatment of the cardiac myocytes with pertussis toxin or PD98059 attenuated the SPC-induced hypertrophic growth response. Further, stimulation with SPC increased phosphorylation of mitogen-activated protein kinase (MAPK) and stimulated MAPK enzyme activity. Finally, endothelin-l stimulated the generation of SPC in cardiac myocytes. The observation that SPC induces a hypertrophic growth response in cardiac myocytes suggests that SPC may play a critical role in the development of cardiac hypertrophy. The effects of SPC could be mediated, in part, by activation of a G protein-coupled receptor and a MAPK signaling cascade.
  • 倉林 正彦, 永井 良三
    医学のあゆみ 191(5) 327-331 1999年10月30日  
  • 石見 拓, 久保田 幸夫, 間仁田 守, 岩崎 俊彌, 金子 克己, 本間 学, 永井 良三
    Japanese circulation journal 63(3) 850-850 1999年10月20日  
  • Y Aihara, M Kurabayashi, M Arai, L Kedes, R Nagai
    BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION 1447(2-3) 318-324 1999年10月  
    A full-length rabbit cDNA of cardiac adriamycin responsive protein (CARP) has been cloned. It shows high levels of identity at the amino acid sequence level (&gt; 86%) with the rat, mouse and human homologues. CARP mRNA levels are highly regulated in adriamycin-cardiomyopathy in rabbits. (C) 1999 Elsevier Science B.V. All rights reserved.
  • H Sumino, S Ichikawa, T Kanda, T Sakamaki, T Nakamura, K Sato, I Kobayashi, R Nagai
    American journal of hypertension 12(10 Pt 1) 1044-7 1999年10月  査読有り
    Hormone replacement therapy (HRT) reduces the incidence of cardiovascular disease (CVD) in postmenopausal women (PMW). Recently, it has been reported that HRT declines angiotensin converting enzyme (ACE) activity, which may be one of the factors protecting against CVD. We measured the plasma levels of bradykinin, which would be expected to increase because the bradykinin-degrading enzyme (kinase II) is the same as ACE. Treatment with conjugated estrogens (0.625 mg/day) and medroxyprogesterone (2.5 mg/ day) was given for 3 months as HRT to 19 hypertensive and 19 normotensive PMW. Plasma bradykinin and ACE activity levels were measured at baseline and after 3 months of HRT. The plasma levels of ACE activity in both the hypertensive and normotensive PMW were significantly reduced by HRT. The plasma levels of bradykinin in the hypertensive PMW were significantly increased by HRT, whereas the administration of HRT tended to increase plasma levels of bradykinin in the normotensive PMW. The increased bradykinin levels with a concomitant decrease of plasma ACE activity by HRT in hypertensive PMW seem to be beneficial for reducing the risk of CVD.
  • N Kubota, Y Terauchi, H Miki, H Tamemoto, T Yamauchi, K Komeda, S Satoh, R Nakano, C Ishii, T Sugiyama, K Eto, Y Tsubamoto, A Okuno, K Murakami, H Sekihara, G Hasegawa, M Naito, Y Toyoshima, S Tanaka, K Shiota, T Kitamura, T Fujita, O Ezaki, S Aizawa, R Nagai, K Tobe, S Kimura, T Kadowaki
    MOLECULAR CELL 4(4) 597-609 1999年10月  
    Agonist-induced activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) is known to cause adipocyte differentiation and insulin sensitivity. The biological role of PPAR gamma was investigated by gene targeting. Homozygous PPAR gamma-deficient embryos died at 10.5-11.5 dpc due to placental dysfunction. Quite unexpectedly, heterozygous PPAR gamma-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet. These phenotypes were abrogated by PPAR gamma agonist treatment. Heterozygous PPAR gamma-deficient mice showed overexpression and hypersecretion of leptin despite the smaller size of adipocytes and decreased fat mass, which may explain these phenotypes at least in part. This study reveals a hitherto unpredicted role for PPAR gamma in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPAR gamma.
  • K Kawai-Kowase, H Kurabayashi, Y Hoshino, Y Ohyama, R Nagai
    CIRCULATION RESEARCH 85(9) 787-795 1999年10月  
    We have recently demonstrated that a developmentally regulated zinc finger protein, basic transcription regulatory element binding protein 2 (BTEB2), is induced in neointimal smooth muscle in response to vascular injury. In this study, we investigated the molecular mechanisms regulating BTEB2 expression in vascular smooth muscle cells (SMCs) in vitro, BTEB2 mRNA expression is rapidly and persistently induced in SMCs by phorbol 12-myristate 13-acetate (PMA) and basic fibroblast growth factor. We have isolated and characterized the promoter region of the human BTEB2 gene to determine the regulatory network controlling expression of this gene in vascular SMCs. Functional studies on the BTEB2 promoter coupled to a luciferase reporter gene demonstrated activation of the promoter by PMA and basic fibroblast growth factor. Both characterization of DNA-protein complexes in vitro and site-specific mutation analysis of the BTEB2 promoter have defined a 9-bp sequence, 5'-CGCCCGCGC-3', located at -25, as the Egr-1 binding site mediating an induction of the BTEB2 promoter activity by PMA. In addition, we show that this site mediates inducible expression through the mitogen-activated protein kinase pathways. These results indicate that BTEB2 is a target of the early-response gene Egr-1, and mitogen-activated protein kinase pathways directly or indirectly activate BTEB2 expression, Given a rapid induction of Egr-1 on stimulation with growth factors or injury, these findings may represent at least one of the molecular mechanisms underlying phenotypic modulation of smooth muscles after vascular injury.
  • T Suzuki, H Katoh, R Nagai
    Japanese heart journal 40(5) 527-34 1999年9月  査読有り
    Aortic dissection is an acute cardiovascular disease associated with high mortality and morbidity. Although uncommon, recent studies have shown that the incidence of this catastrophic disease is steadily increasing. Unfortunately, the disease is still not well recognized on clinical presentation due to lack of specific signs and symptoms. As early diagnosis and initial management are critical for survival, we focused on developing a biochemical diagnostic approach for this disease given its meritorious properties in use in the acute clinical situation and additional projected combined use with established imaging modalities. Studies using an assay developed against smooth muscle myosin heavy chain, a protein which is released from the aortic medial smooth muscle cells on insult to the aortic wall, showed promising results for use of this assay in the diagnosis of aortic dissection. The background of this pioneering assay in addition to its clinical use are discussed in this review.
  • 宇都木 敏浩, 大野 富雄, 伊藤 嘉人, 加藤 典弘, 大山 良雄, 伊藤 弘磨, 内山 強, 倉林 正彦, 河津 捷二, 永井 良三, 伴野 祥一, 山縣 文夫, 宇都木 憲子, 高橋 京一, 岸 章治
    日本眼科紀要 = Folia ophthalmologica Japonica 50(8) 627-631 1999年8月28日  
  • Y Seko, N Takahashi, H Sabe, K Tobe, T Kadowaki, R Nagai
    Biochemical and biophysical research communications 262(1) 290-6 1999年8月19日  査読有り
    We previously reported that hypoxia caused rapid activation of RAS/mitogen-activated protein kinase (MAPK) pathway, two other stress-activated MAPK family members, stress-activated protein kinase (SAPK) and p38MAPK, and Src family tyrosine kinases, p60(c-src) and p59(c-fyn) in cultured rat cardiac myocytes. In this study, to elucidate how hypoxia affects adhesive interaction between cardiac myocytes and extracellular matrix (ECM), we investigated the molecular mechanism of the activation of focal adhesion-associated tyrosine kinases p125(FAK) and paxillin. Here, we show that hypoxia induced tyrosine phosphorylation of p125(FAK) and paxillin and that hypoxia-induced activation of p125(FAK) was accompanied by its increased association with adapter proteins Shc and GRB2, and non-receptor type tyrosine kinase p60(c-src). Furthermore, hypoxia caused subcellular translocation of p125(FAK) from perinuclear sites to the focal adhesions. These results strongly suggest that p125(FAK) is one of the most important components in hypoxia-induced intracellular signaling in cardiac myocytes and may play a pivotal role in adhesive interaction between cardiac myocytes and ECM.
  • 速水 紀幸, 山下 武志, 笠岡 祐二, 福井 栄一, 守随 豊, 永井 良三, 小俣 政男, 村川 裕二
    心電図 19(5) 530-530 1999年8月  
  • 山下 武志, 村川 裕二, 速水 紀幸, 福井 栄一, 笠岡 祐二, 守随 豊, 永井 良三, 小俣 政男
    心電図 19(5) 530-530 1999年8月  
  • H Itoh, T Utsugi, Y Ohyama, T Uchiyama, T Ohno, N Katoh, S Tomono, S Kawazu, R Nagai
    DIABETOLOGIA 42 A326-A326 1999年8月  
  • T Utsugi, T Kanda, Kobayashi, I, T Uchiyama, H Ito, Y Ohyama, S Tomono, S Kawazu, R Nagai
    DIABETOLOGIA 42 A103-A103 1999年8月  
  • S Hiroi, H Harada, H Nishi, M Satoh, R Nagai, A Kimura
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 261(2) 332-339 1999年8月  
    To reveal genetic risk factors of nonfamilial idiopathic cardiomyopathy (IDC) in Japanese, polymorphisms in the SOD2 and HLA-DRB1 genes were investigated in 86 patients and 380 healthy controls. There was a significant excess of homozygotes for the V allele [Val versus Ala (A allele), a polymorphism in the leader peptide of manganese superoxide dismutase at position 16] of the SOD2 gene in the patients compared with the controls (87.2% versus 74.7%, odds ratio = 2.30, p = 0.013, pc &lt; 0.03), and a significant increase in the frequency of HLA-DRB1*1401 in the patients was confirmed (14.0% vs 4.5%, odds ratio = 3.46, p = 0.001, pc &lt; 0.03). A two-locus analysis suggested that these two genetic markers (SOD2-VV genotype and DRB1*1401) may play a synergistic role in controlling the susceptibility to nonfamilial IDC. In addition, processing efficiency of Val-type SOD2 leader peptide in the presence of mitochondria was significantly lower than that of the Ala-type by 11 +/- 4%, suggesting that this lower processing efficiency was in part an underlying mechanism of the association between the SOD2-VV genotype and nonfamilial IDC. (C) 1999 Academic Press.
  • S Watanabe, A Osa, T Sekine, NS Ishioka, M Koizumi, T Kojima, A Hasegawa, M Yoshii, E Okamoto, K Aoyagi, A Miyajima, R Nagai
    APPLIED RADIATION AND ISOTOPES 51(2) 197-202 1999年8月  
    A coronary stent was made radioactive by implantation of Xe-133 ions for the purpose of suppressing the renarrowing of the part of blood vessel in which the stent is implanted. Electrons of relatively low energies emitted in the decay of Xe-133 may give an antiproliferative effect of ionizing radiation to the intimal cells within a limited range of 1 mm. A Xe-133(+) beam accelerated at 40 or 60 keV was directed to several stainless steel stents mounted on a target-holder table that could revolve and move up and down to distribute the Xe-133(+) ions within a stent as well as among the stents. The radioactive stents produced contained up to 100 kBq of Xe-133 and were implanted into the abdominal aortas of rabbits. Neointimal thickening was analyzed by histomorphometry for samples taken 4 weeks after stent implantation. The results indicate that the radioactive stents have a potential to suppress neointimal hyperplasia in rabbits. (C) 1999 Elsevier Science Ltd. All rights reserved.
  • H Sakamoto, T Sakamaki, T Kanda, M Kurabayashi, R Nagai, J Fujii
    Angiology 50(8) 683-7 1999年8月  査読有り
    Loculation of a pleural effusion within an interlobar fissure as a result of congestive heart failure is a well-known entity. It has been termed "vanishing" or "phantom" tumor because its roentgenographic appearance simulates a pulmonary tumor and resolves with treatment of the congestive heart failure. The authors describe an 89-year-old man with a loculated pericardial effusion on the left cardiac border on chest roentgenogram. This was initially thought to represent an occult metastatic malignancy; however, its etiology became obvious when it disappeared with therapy of heart failure. Loculated pericardial effusion should be included in the differential diagnosis of roentgenographic densities in the chest when seen on the left cardiac border.
  • S Saito, R Aikawa, I Shiojima, R Nagai, Y Yazaki, I Komuro
    FEBS letters 456(1) 103-7 1999年7月30日  査読有り
    We here examined the role of the interleukin-6 (IL-6) family of cytokines in endothelin-1 (ET-1)-induced hypertrophic responses using cultured cardiac myocytes of neonatal rats. ET-1 induced expression of IL-6 and leukemia inhibitory factor (LIF) genes. ET-1-induced LIF gene expression was abolished by inhibition of protein kinase C activity. ET-1 activated the promoter of atrial natriuretic peptide and beta-type myosin heavy chain genes through the tyrosine kinase pathway and IL-6 receptor gp130. These results suggest that the IL-6 family of cytokines mediates ET-1-induced expression of some fetal genes in cardiac myocytes.
  • N Watanabe, M Kurabayashi, Y Shimomura, K Kawai-Kowase, Y Hoshino, I Manabe, M Watanabe, M Aikawa, M Kuro-o, T Suzuki, Y Yazaki, R Nagai
    Circulation research 85(2) 182-91 1999年7月23日  査読有り
    We have recently characterized the promoter region of the rabbit embryonic smooth muscle myosin heavy chain (SMemb/NMHC-B) gene and identified the 15-bp sequence, designated SE1, located at -105 from the transcriptional start site as an important regulatory element for its transcriptional activity in a smooth muscle cell (SMC) line. In this study, we attempted to isolate cDNA clones encoding for the transcription factors that control the expression of the SMemb gene through binding to this cis-regulatory element. We screened a lambdagt11 cDNA library prepared from C2/2 cells, a rabbit-derived SMC line, by using a radiolabeled concatenated oligonucleotide containing SE1 as a probe. Sequence analysis revealed that one of the cDNA clones corresponds to the rabbit homologue of basic transcriptional element binding protein-2 (BTEB2), which has previously been identified as one of the Krüppel-like transcription factor. Gel mobility shift assays and antibody supershift analyses with nuclear extracts from C2/2 cells indicate that BTEB2 is a major component of nuclear factor:SE1 complexes. Furthermore, a glutathione S-transferase-BTEB2 fusion protein binds to the SE1 in a sequence-specific manner. In support of the functionality of BTEB2 binding, basal promoter activity and BTEB2-induced transcriptional activation were markedly attenuated by the disruption of the SE1. In adult rabbit tissues, BTEB2 mRNA was most highly expressed in intestine, urinary bladder, and uterus. BTEB2 mRNA levels were downregulated in rabbit aorta during normal development. Moreover, immunohistochemical analysis indicated a marked induction of BTEB2 protein in the neointimal SMC after balloon injury in rat aorta. These results suggest that BTEB2 mediates the transcriptional regulation of the SMemb/NMHC-B gene and possibly plays a role in regulating gene expression during phenotypic modulation of vascular SMC.
  • H Kurihara, Y Kurihara, R Nagai, Y Yazaki
    Cellular and molecular biology (Noisy-le-Grand, France) 45(5) 639-51 1999年7月  査読有り
    A series of gene targeting research have revealed novel roles of endothelins (ETs), peptides with potent vasoconstrictive and proliferative activities, in neural crest development in mammals. The phenotype of mice lacking the ET-1/ET-A receptor-mediated signalling affects cranial/cardiac neural crest-derived structures including the branchial arches and great vessels, and is highly similar to a set of the phenotypes of the avian neural crest ablation model. In contrast, mice lacking the ET-3/ET-B receptor-mediated signalling have defects in enteric neurons and melanocytes derived from trunk/vagal neural crest, resulting in megacolon and coat color spotting. Thus, both distinct pathways of the ET system seem to participate in the normal development of different neural crest lineages. Moreover, mutations in the human ET-3 and ET-B receptor genes have been identified in patients with Hirschsprung disease. As for the mechanisms involving the ET system in neural crest development, HANDs and Goosecoid, transcriptional factors essential for embryogenesis, have been suggested as key molecules downstream to the ET-mediated signalling in cranial/cardiac neural crest.
  • H Sumino, K Satö, T Sakamaki, T Kanda, T Nakamura, T Takahashi, H Sakamoto, I Kobayashi, R Nagai
    Journal of human hypertension 13(7) 437-42 1999年7月  査読有り
    OBJECTIVE: To examine the influence of systemic nitric oxide (NO) synthesis on blood pressure in patients with chronic renal failure undergoing haemodialysis, since nitric oxides are susceptible to renal excretion or are dialysed, a different indicator that is unaffected by renal function, such as the level of exhaled NO was evaluated. We examined the levels of the endogenous NO before and after a haemodialysis session. DESIGN AND METHODS: We evaluated the serum concentrations of nitrite/nitrate and the rate of nitric oxide release into exhaled air in 10 patients with hypertension who were receiving maintenance haemodialysis. RESULTS: The serum concentrations of nitrite/nitrate before haemodialysis were significantly higher than those in 10 normal controls (183 +/- 151 microM vs 42 +/- 17 microM, P < 0.05). These levels decreased significantly by the end of haemodialysis (42 +/- 26 microM). Because the amount of nitric oxide in the deepest expirate correlated well with the duration of exhalation, we were able to derive the rate of release of NO. The rate of NO release was 0.034 +/- 0.012 nmol/sec before haemodialysis, similar to that in normal controls (0.031 +/- 0.013nmol/sec). The rate was significantly reduced after dialysis (0.023 +/- 0.010 nmol/sec) (P < 0.05). The mean pre-dialysis mean blood pressure (109 +/- 11 mm Hg) and the post-dialysis blood pressure (106 +/- 9 mm Hg) were the same. CONCLUSIONS: These data indicate that NO production does not appear to have a critical role in control of arterial blood pressure across haemodialysis in patients with chronic renal failure.
  • N Koitabashi, T Utsugi, R Seki, E Okamoto, Y Sando, Y Kaneko, R Nagai
    JAPANESE CIRCULATION JOURNAL-ENGLISH EDITION 63(7) 572-575 1999年7月  
    A 23-year-old woman with heterozygous Fabry's disease who had acroparesthesia was admitted to hospital for precise examination of the disease before childbearing. She had no cardiac-related symptoms and no abnormality on physical examination. The alpha-galactosidase A activity in her leukocytes was present, but lower than normal. However, the endomyocardial biopsy showed specific changes for Fabry's disease. As Fabry's disease is a ran X-linked recessive inborn error of glycosphingolipid metabolism, heterozygous females are usually asymptomatic, but rarely can be affected as severely as hemizygous males. This is an isolated case of heterozygous Fabry's disease in a female in whom cardiac involvement was detected by endomyocardial biopsy, although she had no cardiac abnormality on physiological examinations. In conclusion, endomyocardial biopsy is useful for evaluation of the cardiac involvement of Fabry's disease even in an asymptomatic case.
  • A Yoshida, T Kanda, H Sakamoto, H Masuda, T Iwasaki, T Nakajima, I Kobayashi, R Nagai
    Angiology 50(7) 607-11 1999年7月  査読有り
    The authors report a rare case of a malignant hemangioendothelioma (MH) originating in the pericardium. In this case, a metastatic skin lesion was found first, and subsequently the existence of a primary cardiac lesion was confirmed. Generally, primary cardiac tumors grow slowly, and the prognosis of MH is relatively good. In this case, however, the patient died suddenly during the creation of a pericardial window for drainage. An autopsy showed that the MH originated from a pericardial lesion in the right atrium.

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