Abstract 279: A Novel eNOS-Independent Protective Action of Statin Against Angiotensin II-Induced Cardiovascular Remodeling
Background: Statin is known to have pleiotropic actions mainly through activation and up-regulation of the eNOS system. However, the mechanism by which statin prevents cardiovascular remodeling caused by renin-angiotensin activation remains unknown. Methods and Results: We used pitavastatin because this statin is not metabolized by hepatic cytochrome P450 after absorption from the small intestine, suggesting that pitavastatin has direct action on the cardiovascular system. C57BL6/J mice at 10 weeks of age were infused with Ang II (2.0 mg/kg/day) by an osmotic mini-pump for 2 weeks and were simultaneously administered pitavastatin (0.2 mg/kg/day) or a vehicle. Echocardiography showed that both relative wall thickness and left ventricular mass index were significantly smaller in pitavastatin-treated mice, and E/A ratio in transmitral doppler flow, a parameter of left ventricular diastolic function, was significantly higher in pitavastatin-treated mice than in vehicle-treated mice. Enhancement of perivascular fibrosis and medial thickness of the coronary artery, of cardiac fibrosis, and of cardiomyocyte hypertrophy by Ang II treatment were all significantly attenuated in pitvastatin-treated mice compared to those in vehicle-treated mice. Pitavastatin treatment also reduced urinary excretion of 8-OHdG and cardiac mRNA expression of NADPH oxidase subunit p67phox. The enhanced cardiac TGFβ-1 expression and Smad2 phosphorylation by Ang II were attenuated by pitavastatin treatment. In eNOS KO mice, pitavastatin reduced Ang II-induced structural and functional cardiac remodeling, including pericoronary fibrosis, cardiac hypertrophy, cardiac fibrosis and left ventricular diastolic dysfunction. Survival rate of eNOS KO mice was decreased by Ang II treatment; however, pitavastatin significantly improved the survival rate of Ang II-treated eNOS KO mice. Conclusion: Pitavastatin has a novel protective action against Ang II-induced cardiac remodeling through decreasing oxidative stress and suppressing the TGFβ-Smad pathway. Furthermore, this protective action of pitavastatin is independent of eNOS activation.