Abstract 1603: Statins Pleiotropically Mitigate LOX-1 and Cav-1 by Upregulating Hemeoxygenase-1/HSP-90 for e-NOS Phosphorylation and Reduced Ventricular Remodeling during Hypercholesterolemia
Statin based lowering of low density lipoprotein (LDL) cholesterol has been considered as one of the major factors of cardiovascular risk reduction. Independent of lipid lowering, statins up-regulates the endothelial nitric oxide production through caveolin-1 (Cav-1) downregulation. The novel receptor, lectin like Ox-LDL receptor-1 (LOX-1) is known to bind, internalize and degrade Ox-LDL for its action. This study was designed to investigate the molecular mechanism of statin mediated Cav-1 & LOX-1 regulation. Rats were randomized into: control (normal diet); HC (5% high cholesterol diet for 8 weeks) and HC + Pravastatin (S) (1mg/kg) administered orally for 2 weeks (HCS). Statin reduced the cholesterol, LDL & increased the HDL levels compared to non-treated HC. Hearts were subjected to permanent left anterior descending coronary artery occlusion (MI). LV functions by echocardiography was examined 30 days after MI. Decreased LV inner diameter (7.4 vs 9 mm), increased ejection fraction (47 vs 39 %) and fractional shortening (25 vs 20 %) was observed in HCS compared to HC. Cav-1, LOX-1 protein expression was upregulated in HC (2, 1.8 fold) compared to control which were decreased to 1.2 and 1.1 fold on statin treatment. We have observed in HCS increased Heme Oxygenase-1 (HO-1, 1.9 fold), HSP-90 expression (1.7 fold) and phosphorylation of eNOS (p-eNOS) by 1.6 fold whereas in HC 0.4, 0.5 and 0.4 fold respectively as compared to control. Over expression of HO-1 and HSP-90 by statin treatment might have facilitated for the stimulated displacement of eNOS from Cav-1 for its activation. Further to examine how HO-1 and HSP-90 regulate the eNOS activation we have generated cardiac specific HO-1 over expressed mice. Immunohistochemical analysis of HO-1 mice clearly demonstrated decreased Cav-1-eNOS interaction and increased p-eNOS (1.8 fold) as shown by immunoblot analysis compared to wild type. Moreover, we observed increased HSP-90 (2 fold) which is known for the serine phosphorylation of eNOS. These results indicate for the first time; a novel mechanism of action by statins in regulation of the caveolar platform by Cav-1, LOX-1, HO-1/HSP-32 & HSP-90 for eNOS activation which would be a novel treatment strategy to prevent HC mediated cardiovascular complications.