［総説］生体内における一酸化窒素合成酵素システムの意義の解明
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概要
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The nitric oxide (NO) synthases (NOSs) system consists of three different isoforms, including neuronal (nNOS), inducible (iNOS), and endothelial NOSs (eNOS). The roles of NO in vivo have been extensively investigated in pharmacological studies with NOS inhibitors. However, the NOS inhibitors possess multiple non-specific actions. Indeed, we clarified that vascular lesion formation caused by long-term treatment with the NOS inhibitors is not solely mediated by simple inhibition of vascular NO synthesis. Thus, the authentic roles of endogenous NO in our body still remain to be fully elucidated. To address this important issue, we have successfully developed mice in which all three NOS isoforms are completely disrupted. While the triply n/i/eNOS^<-/-> mice were unexpectedly viable and appeared normal, their survival and fertility rates were markedly reduced as compared with wild-type mice. Intriguingly, the triply n/i/eNOS^<-/-> mice, but not singly eNOS^<-/-> mice, spontaneously developed myocardial infarction accompanied by severe coronary arteriosclerotic lesions. Furthermore, the triply n/i/eNOS^<-/-> mice manifested abnormalities in a variety of systems, including the central nervous system, metabolic system, and bone system. These results provide the first evidence that genetic disruption of all three NOS genes causes a variety of disorders in mice in vivo, demonstrating a critical role of the endogenous NOS system in maintaining body homeostasis.
- 琉球医学会の論文