| Project/Area Number |
17390071
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | University of Occupational and Environmental Health, Japan |
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Principal Investigator |
TSUTSUI Masato University of Occupational and Environmental Health, Japan, School of Medicine, Department of Pharmacology, Associate Professor (70309962)
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| Co-Investigator(Kenkyū-buntansha) |
SHIMOKAWA Hiroaki Tohoku University Graduate School of Medicine, Deparment of Cardiovascular Medicine, Professor (00235681)
UETA Yoichi University of Occupational&Environmental Health, Japan, School of Medicine, Department of Physiology, Professor (10232745)
YANAGIHARA Nobuyuki University of Occupational&Environmental Health, Japan, School of Medicine, Department of Pharmacology, Professor (80140896)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥11,770,000 (Direct Cost: ¥10,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2007: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2006: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2005: ¥5,000,000 (Direct Cost: ¥5,000,000)
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| Keywords | nitric oxide synthase / genetically engineered mice / arteriosclerosis / myocardial infarction / metabolic syndrome / 一酸化窒素 / ノックアウト / 骨 / マウス / 遺伝子改変 / 尿崩症 / メタボリック症候群 |
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| Research Abstract |
The nitric oxide synthase (NOS) system consists of three isoforms: neuronal (nNOS), inducible (iNOS), and endothelial NOS (eNOS). The roles of the NOS system in vivo have been widely studied using non-selective NOS inhibitors. However, since the NOS inhibitors possess multiple non-specific actions, the authentic roles of the NOS system in our body remain to be fully elucidated. To address this issue, we have recently developed the NOS system-deficient mice (triply n/i/eN0S^<-/-> mice) (PNAS 2005).
Although the triply NOS^<-/-> mouse was not embryo-lethal fortunately, survival rate was markedly reduced as compared with wild-type mice. Intriguingly, more than half of the triply NOS4^<-/-> mice died due to spontaneous myocardial infarction associated with severe coronary arteriosclerosis.
Notably, although it is well established that eNOS exerts antiarteriosclerotic effects, and although eNOS^<-/-> mice manifest accumulation of cardiovascular risk factors, eNOS^<-/-> mice do not spontaneous
… More
ly develop arteriosclerotic vascular lesion formation. This inconsistency is explained by a compensatory mechanism by other NOSs that are not genetically disrupted. Thus, our triply NOS^<-/-> mouse is a powerful experimental tool to solve this problem and to investigate the roles of the NOS system.
The triply NOS^<-/-> mice manifested metabolic syndrome, including visceral obesity, hypertension, hypertriglyceridemia, and impaired glucose tolerance. In addition, the triply NOS mice exhibited left ventricular hypertrophy and diastolic dysfunction. Importantly, an increase in plasma angiotensin II level and upregulation of cardiac angiotensin-converting enzyme were noted in the triply NOS^<-/-> mice, suggesting an involvement of activation of the renin-angiotensin system in the pathogenesis of cardiovascular disorders in the triply NOS^<-/-> mice.
These results provide the first direct evidence that genetic disruption of the whole NOS system causes spontaneous myocardial infarction associated with multiple cardiovascular risk factors of metabolic origin in mice in vivo, demonstrating the critical role of the endogenous NOS system in maintaining cardiovascular homeostasis. Less
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