Abstract 1500: Gender Differences of Arteriosclerotic Cardiovascular Diseases in Mice Lacking All Nitric Oxide Synthase Isoforms
Background: We have recently succeeded in developing mice lacking all 3 nitric oxide synthase (NOS) isoforms (triply n/i/eNOS-KO mice) (PNAS 2005). Our preliminary study has revealed that those mice spontaneously develop cardiovascular diseases, including hypertension, dyslipidemia, and myocardial infarction (MI), and that there seems to be a great gender difference in those disorders.
Methods and Results: Experiments were performed in both genders of wild-type (WT) and triply-KO mice. In male mice, survival rate at 11 months of age was markedly more reduced in triply-KO mice than in WT mice (15% vs. 100%, P<0.001, n=34 – 41), whereas in female mice, the survival rate was slightly but significantly more reduced in triply-KO mice than in WT mice (74% vs. 100%, P<0.05, n=34–38). There was a significant gender difference in the survival rate in the triply-KO mice (male 15% vs. female 74%, P<0.05). A postmortem examination revealed that both genders of the triply-KO mice died mainly due to spontaneous MI associated with severe coronary arteriosclerosis (n=13–20). However, in the female triply-KO mice, as compared with the male triply-KO mice, the incidence of MI (29% vs. 56%, P<0.05) and the extent of coronary lesions (intima/media ratio, 0.15±0.01 vs. 0.01±0.01, P<0.05) were both significantly less. In addition, although both genders of the triply-KO mice exhibit hypertension (HT) and hyper-low density lipoproteinemia (hyperLDL), the extents of both HT (135±2 vs. 150±3 mmHg) and hyperLDL (20.6±3.9 vs. 29.4±7.9 mg/dl) were again significantly less in the female than the male mice (both P<0.05, n=6–10). Importantly, ovariectomy significantly exacerbated both HT (159±3) and hyperLDL (32.1±8.8) in the female triply-KO mice (both P<0.05, n=6–7). Furthermore, treatment with 17β-estradiol (10−8 M, 2 days) significantly enhanced prostacyclin production in isolated aortas of the triply-KO mice (3.07±0.44 to 6.56±0.56 nM/g, P<0.05, n=5), suggesting a novel NO-independent anti-atherogenic action of estrogen.
Conclusions: These results provide the first evidence that the gender difference in the extent of arteriosclerotic cardiovascular diseases still exists even in the complete absence of NOSs system, in which estrogen may, at least in part, be involved.