Abstract 15963: Caveolin-3 Overexpression Attenuates Angiotensin-II Induced Cardiac Hypertrophy via Inhibition of Protein Kinase C Modulation of T-Type Ca2+ Current in Ventricular Myocytes
Chronic angiotensin II (AngII) activation results in pathologic cardiac hypertrophy, heart failure and arrhythmia through the activation of reexpressed T-type Ca2+ channel (TTCC) current (ICa,T). We have shown that cardiac TTCCs localize to caveolae and caveolin-3 (Cav3) specifically inhibits ICa,T in ventricular myocytes. Caveolae localize many signaling molecules including receptors, kinases, ion channels and enable compartmentalized regulation of signaling pathways. We hypothesized that Cav3 and caveolae are essential for protective signaling in pathological cardiac hypertrophy. We used AngII infusion or transverse aortic constriction (TAC) model of cardiac hypertrophy in wild type (WT) or cardiac specific Cav-3 OE mice. Four weeks of AngII infusion or TAC in mice resulted in reduced fractional shortening, ejection fraction and increase in LV wall thickness. A significant reduction in the expression of Cav3 was also observed in hypertrophic ventricular myocytes. Cav3 co-immunoprecipitated the angiotensin type-1 receptor and protein kinase Cα (PKCα) from control myocytes but not from hypertrophic ventricular myocytes. Whole cell patch clamp analysis demonstrated expression of the ICa,T in ventricular myocytes at 4 weeks of TAC (2 ± 0.5 pA/pF) or Ang-II infusion (0.6 ± 0.2 pA/pF). In contrast, the Cav3 OE and sham mice did not express ICa,T and had normal cardiac function. Interestingly, ICa,T was detected only when Cav3 expression was reduced following TAC at 4 weeks or longer. To determine the role of Cav3 in AngII stimulation of ICa,T we treated cultured neonatal myocytes with 10 µM AngII, which caused a significant increase in ICa,T (175%). siRNA mediated knockdown of Cav3 further increased AngII stimulation of ICa,T (460%). The PKCα inhibitor Ro-31-0822 treatment caused a complete inhibition of the AngII stimulation of ICa,T. Similarly overexpression of Cav3 also resulted in complete inhibition of the AngII stimulation of ICa,T Our data show that reduced Cav3 expression in cardiac hypertrophy results in AngII stimulation of ICa,T via PKCα activation and Cav3 overexpression prevents this effect. We conclude that Cav3 expression is critical to protective signaling in the ventricular myocytes in the setting of cardiac hypertrophy.
- © 2011 by American Heart Association, Inc.