The major findings of our study are: 1) the absence of iNOS failed to protect mice against endothelial dysfunction or accelerated thrombosis produced by hyperhomocysteinemia; and 2) deficiency of iNOS exacerbated, rather than protected against myocardial ischemia-reperfusion injury and cardiac oxidative stress in hyperhomocysteinemic mice. Here, NOS2 is linked to endothelial dysfunction.