Nitric oxide (NO) is synthesized by three different NO synthase (NOS) isoforms, including neuronal (nNOS), inducible (iNOS), and endothelial NOS (eNOS). The roles of the NOS system in vivo have been extensively investigated in pharmacological studies with non-selective NOS inhibitors such as L-NAME and L-NMMA. However, because the NOS inhibitors possess multiple non-specific actions, the authentic roles of the NOS system in our body still remain to be fully elucidated. To address this important issue, we have successfully developed genetically manipulated mice in which all three NOS genes are totally 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 spontaneously developed acute myocardial infarction accompanied by severe coronary arteriosclerotic lesions. Furthermore, the triply n/i/eNOS
-/- mice manifested metabolic syndrome, dyslipidemia, and diastolic heart failure. These results provide the first evidence that genetic disruption of all NOS genes causes a variety of cardiovascular diseases in mice
in vivo, demonstrating a critical role for the endogenous NOS system in the pathogenesis of cardiovascular disorders.
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