2) (35). These results indicate that NOSs in bone marrow cells

exert an inhibitory effect on vascular lesion formation caused by blood flow disruption in mice in vivo, Wnt inhibitor demonstrating a novel vasculoprotective role of NOSs in bone marrow-derived vascular progenitor cells. During 11 months of follow-up, all (100%) of the wild-type mice lived, whereas only 15% of the triple NOSs null mice survived (Fig. 3A) (33). The survival rate was significantly worse in accordance with the number of disrupted NOS genes in the order of single, double, and triple NOSs null mice. Postmortem examination revealed that 55% of the triple NOSs null mice died of myocardial infarction (Fig. 3 and Fig. 4A) (33). This is the first demonstration to show that a deficiency of NOSs leads to the development of spontaneous myocardial infarction. In the coronary arteries of the dead triple NOSs null mice, marked intimal formation, medial thickening, and mast cell infiltration were noted, while intra-coronary thrombus was rarely observed

Sirolimus (Fig. 4A–C) (33). Histamine released from adventitial mast cells is thought to cause coronary vasospasm with resultant myocardial infarction in humans (36). It is thus possible that coronary intimal hyperplasia, medial thickening, and vasospasm are involved in the pathogenesis of myocardial infarction in the triple NOSs null mice. Although human myocardial infarction mainly results from rupture of atherosclerotic plaques and subsequent thrombus formation, the triple NOSs null mice seem to be a model of non-atherosclerotic forms of acute myocardial infarction in humans. In the triple NOSs null mice, there was a complete lack of endothelium-dependent relaxations to acetylcholine, which is a physiological ADP ribosylation factor eNOS activator, and contractions to phenylephrine, which is an α1 adrenergic

receptor agonist, were markedly potentiated (33). Thus, vascular dysfunction could also be involved in the pathogenesis of myocardial infarction in the triple NOSs null mice. The renin-angiotensin system was markedly activated in the triple NOSs null mice, and long-term treatment with an angiotensin II type 1 (AT1) receptor blocker olmesartan potently inhibited coronary arteriosclerotic lesion formation, vascular mast cell infiltration, and the occurrence of myocardial infarction in those mice, with a resultant improvement of the prognosis (33). These results suggest that the AT1 receptor pathway is involved in the occurrence of spontaneous myocardial infarction in the triple NOSs null mice.