Abstract 1428: Genetic Disruption of All Nitric Oxide Synthase Isoforms Markedly Reduces Survival due to Myocardial Infarction in Male Mice
Background: Nitric oxide (NO) is synthesized by three different isoforms of NO synthase, including neuronal (nNOS), inducible (iNOS), and endothelial NOS (eNOS). We have recently succeeded in developing mice lacking all three NOS isoforms (PNAS 2005). In this study, we examined whether or not the survival of the triply n/i/eNOS−/− mice is reduced, and if so, to elucidate the cause of death in those mice.
Methods: Experiments were performed in both gender of the following 9 strains: wild-type C57BL and 129SV mice, singly nNOS−/−, iNOS−/−, eNOS−/−, doubly n/iNOS−/−, n/eNOS−/−, i/eNOS−/−, and triply n/i/eNOS−/− mice (n=18~57). Their survival rate was followed up for 11 months. The cause of death was identified by a postmortem examination.
Results: During the 11 months of follow-up, all (100%) of male wild-type C57BL (n=41) and 129SV mice (n=40) lived, whereas only 15% (5/34) of male triply n/i/eNOS−/− mice survived. Survival rate in male mice was significantly worse in accordance with the number of disrupted NOS genes, in the order of singly (82~87%, P<0.05 each, n=45– 49), doubly (62~68%, P<0.01 each, n=29–57), and triply NOS−/− mice (15%, P<0.001) as compared with the wild-type mice. Similarly, survival rate in female mice was also exacerbated in accordance with the number of disrupted NOS genes (n=18~41), and the survival rate in female triply n/i/eNOS−/− mice (74%, n=34) was significantly reduced compared with female wild-type mice (100%, n=38). However, there was a significant gender difference in survival rate between the male (15%) and the female triply n/i/eNOS−/− mice (74%) (P<0.05). A postmortem examination revealed that more than half (56% 9/16) of the male triply n/i/eNOS−/−mice died due to myocardial infarction associated with severe arteriosclerotic coronary lesions. On the other hand, in the female triply n/i/eNOS−/− mice, the incidence of myocardial infarction (29% 2/7, P<0.05) and the extent of coronary lesions were both less.
Conclusions: These results provide the first evidence that genetic disruption of the whole NOS system results in marked reduction of survival, especially in male mice, mainly due to myocardial infarction, suggesting the critical role of the NOS system to maintain cardiovascular homeostasis in this gender.