Elucidation of the pathogenesis of life style-related diseases and development of their therapeutic strategy

一氧化氮合酶(NOS)系统由三种亚型组成：神经型(NNOS)、诱导型(INOS)和内皮型(ENOS)。使用非选择性一氧化氮合酶抑制剂，已经广泛研究了一氧化氮合酶系统在体内的作用。然而，由于一氧化氮合酶抑制剂具有多种非特异性作用，因此，一氧化氮合酶系统在人体内的真实作用仍有待充分阐明。为了解决这个问题，我们最近开发了一氧化氮合酶系统缺陷小鼠(Triply n/i/enos^&lt；-1-&gt；小鼠)(PNAS 2005)。幸运的是，尽管三重一氧化氮合酶系统缺陷小鼠不是胚胎致死的，但与野生型小鼠相比，存活率显著下降。有趣的是，超过一半的三次…小鼠死于与严重冠状动脉硬化相关的自发性心肌梗死。值得注意的是，尽管eNOS具有抗动脉粥样硬化的作用，尽管eNOS小鼠表现出心血管危险因素的积聚，但eNOS小鼠并不自发地更易发生动脉硬化性血管病变的形成。这种不一致是由其他NOS的补偿机制解释的，这些NOS没有被基因破坏。因此，我们的三重NOS^-/-&gt；小鼠是一个强大的实验工具，可以解决这个问题并研究NOS系统的作用。三重NOS^-/-&gt；小鼠表现出代谢综合征，包括内脏肥胖、高血压、高甘油三酯血症和糖耐量受损。此外，三重NOS^&lt；-/-&gt；小鼠表现出左心室肥厚和舒张期功能障碍。重要的是，在三重小鼠中观察到血浆血管紧张素II水平的升高和心脏血管紧张素转换酶的上调，这表明肾素-血管紧张素系统的激活参与了三重小鼠心血管疾病的发病机制。这些结果提供了第一个直接的证据，证明了在体内整个一氧化氮合酶系统的遗传破坏导致自发性心肌梗死与多种心血管代谢起源的危险因素相关，证明了内源性一氧化氮合酶系统在维持心血管内稳态中的关键作用。较少

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/eNOS^<-1-> 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 NOS^<-/-> 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 spontaneousl … More y 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