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

一氧化氮合酶（nitric oxide synthase，NOS）系统由三种亚型组成：神经型NOS（neuronal NOS）、诱导型NOS（inducible NOS）和内皮型NOS（endothelial NOS，eNOS）。使用非选择性NOS抑制剂已经广泛研究了NOS系统在体内的作用。然而，由于NOS抑制剂具有多种非特异性作用，NOS系统在我们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NOS系统缺陷小鼠（triply n/i/eNOS^<-1->mice）（PNAS 2005）。尽管幸运的是，triply nNOS ^&lt;-/-&gt;小鼠不是胚胎致死的，但与野生型小鼠相比，存活率显著降低。有趣的是，超过一半的三重NOS^&lt;-/-&gt;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，尽管已经充分证实eNOS发挥抗动脉炎作用，尽管eNOS^&lt;-/-&gt;小鼠表现出心血管危险因子的积累，但eNOS*&lt;-/-&gt;小鼠并没有自发性心肌梗死。 ...更多信息 发展为动脉血管病变形成。这种不一致性是由其他未被遗传破坏的NOS的补偿机制解释的。因此，我们的三重NOS^&lt;-/-&gt;小鼠是一个强有力的实验工具，以解决这一问题，并探讨NOS系统的作用。三重NOS^&lt;-/-&gt;小鼠表现出代谢综合征，包括内脏肥胖，高血压，高血糖症，和糖耐量受损。此外，三重NOS^&lt;-/-&gt;小鼠表现出左心室肥大和舒张功能障碍。重要的是，在三重NOS^&lt;-/-&gt;小鼠中注意到血浆血管紧张素II水平的增加和心脏血管紧张素转换酶的上调，提示在三重NOS^&lt;-/-&gt;的心血管疾病的发病机制中参与了肾素-血管紧张素系统的激活。这些结果提供了第一个直接证据，即整个NOS系统的遗传破坏导致自发性心肌梗死与小鼠体内代谢来源的多种心血管危险因素相关，证明了内源性NOS系统在维持心血管稳态中的关键作用。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