Abstract 5553: Hypercholesterolemia Induced Overexpression of Caveolin-1 and LOX-1 Downregulates HO-1/HSP-90 Mediated e-NOS Activation: A Novel Therapeutic Strategy for the Improvement of Left Ventricular Function
Hypercholesterolemia (HC) related decrease in eNOS phosphorylation & endothelial dysfunction may account for impaired angiogenesis and subsequent increased ventricular remodeling. Over expression of Caveolin-1 (Cav-1) and Lectin-like oxidized LDL receptor (LOX-1) has been demonstrated during HC but the mechanism needs to be elucidated. To investigate this we randomized the rats into control (normal diet) and HC (5% high cholesterol diet for 8 weeks). The cholesterol, triglycerides & LDL levels were increased & the HDL levels decreased in HC compared to control. After the experimental diet period the rats were subjected to Left Anterior Descending Artery (LAD) ligation. We evaluated the expression of Cav-1, LOX-1, Heme Oxygenase (HO-1), HSP-90, phospho(p)-Akt & p-eNOS in HC and control. Significant increase in Cav-1, LOX-1 (2, 1.8 fold) & decrease in HO-1, HSP-90, p-Akt, p-eNOS & VEGF (0.5, 0.6, 0.4, 0.5 & 0.6 fold) was observed in HC compared to control. The LV functional reserve was evaluated by measuring the ejection fraction (EF), fractional shortening (FS) & LV internal diameter (LVID) after 30 days of LAD ligation. Significant increase in LVID ( 8.6 vs 7) and decrease in EF (39 vs 53%), FS (20 vs 28%), LVID (2 vs 2.7mm) as well as capillary (1888 vs 2424) & arteriolar density (1.5 vs 2.5) counts/mm2 was observed in HC compared to control. Earlier we have reported that over expression of HO-1 mediates eNOS activation & cardioprotection in MI model. To investigate the mechanism involved in HO-1 mediated cardioprotection we generated cardiac specific HO-1 over expressed transgenic (Tg) mice. Immunohistochemical analysis of HO-1 Tg mice has clearly demonstrated decreased Cav-1-eNOS interaction. Immunoblot analysis has shown to decrease Cav-1 (0.6 fold) & increased HSP-90, p-Akt, p-eNOS & VEGF expression (1.5, 1.6, 1.4 & 1.5 fold) as compared to control. These findings demonstrated that HO-1 over expression regulates HSP-90 & Cav-1 for eNOS activation. In conclusion, we demonstrate a novel mechanism of HO-1/HSP-90 mediated Cav-1-eNOS regulation leading to increased neovascularization & reduced ventricular remodeling during HC for the regression of clinical complications which would be crucial for cardiovascular drug therapy.