Abstract 550: Important Role of Renin-Angiotensin System in the Pathogenesis of Myocardial Infarction in Mice Lacking All Nitric Oxide Synthase Isoforms
Background: We have recently developed mice lacking all 3 nitric oxide synthase (NOS) isoforms (triply n/i/eNOS-KO mice) (PNAS 2005). Our preliminary study has revealed that the triply-KO mice develop spontaneous myocardial infarction (MI). In this study, we examined whether activation of renin-angiotensin (RA) system is involved in the pathogenesis of MI in those mice.
Methods: Male wild-type (WT) and triply-KO mice were followed-up for 11 months. Experiments regarding activation of RA system were performed in the mice at 5 months of age.
Results: During the 11 months of follow-up, all (100%) of WT mice lived (n=41), whereas only 15% of triply-KO mice survived (P<0.001) (n=31). A postmortem examination revealed that the triply-KO mice died mainly due to MI associated with severe coronary arteriosclerosis (n=20). In the triply-KO mice, significant increases in plasma angiotensin II levels (140±16 vs.
38±6 pg/ml), aortic angiotensin-converting enzyme activity (15.0±1.8 vs. 7.0±0.7 units/g), and cardiac angiotensin II type 1 receptor (AT1) expression (AT1/actin, 0.70±0.06 vs. 0.33±0.01) (Western blotting) were noted as compared with the WT mice (all P<0.05). Importantly, long-term treatment with olmesartan (AT1 blocker, 5 mg/kg/day, 10 months, PO) significantly inhibited coronary lesion formation (intima/media ratio, 1.58±0.04 to 0.01±0.01), reduced the incidence of MI (100% to 42%), and improved the prognosis of those mice (15% to 61%), associated with reduction of blood pressure (BP) (150±11 to 122±4 mmHg) (all P<0.05, n=6–12). Although long-term treatment with hydralazine (0.05 mg/ml, 10 months, PO) also significantly reduced BP levels (124±4) to the same extent as with olmesartan, the inhibitory effect of hydralazine on coronary lesion formation (0.04±0.02) was significantly less than that of olmesartan (P<0.05), and hydralazine failed to significantly reduce the incidence of MI or improve the prognosis (n=6–12), suggesting that the beneficial effects of olmesartan are mainly mediated by its non-BP effects.
Conclusions: These results indicate that activation of RA system plays an important role in the pathogenesis of MI in the presence of defective NOSs system, suggesting the therapeutic importance of RA inhibitors to prevent MI in humans.