EXACERBATED RENIN-ANGIOTENSIN SYSTEM INDUCES APOPTOSIS IN SPONTANEOUSLY HYPERTENSIVE RATS AND IN ISOPROTERENOL-INDUCED CARDIAC INJURY VIA CAMKII

VELEZ RUEDA J.O.; MATTIAZZI A.R.; PALOMEQUE J.

Philadelphia

Congreso; ISHR North American Section Meeting; 2011

ISHR

Angiotensin II (Ang II)-induced apoptosis in vitro and ex vivo is mediated by Ca2+-calmodulin-dependent protein kinase II (CaMKII), however, whether the endogenous production of Ang II in vivo induces apoptosis through CaMKII is still matter of study. For this purpose we used two rat models of heart injury with exacerbated rennin-angiotensin-aldosterone system (RAAS), the Spontaneously Hypertensive Rats (SHR) and the Isoproterenol induced cardiac damage (Iso-rats). The SHR showed an increase in aldosterone serum levels (211.2±25.8% from control), as index of the RAAS activity, in blood pressure (84.2±2.6 mmHg above control), in heart hypertrophy (left ventricular mass index, LVMI 8.6±1.1 mg/mm) and in apoptosis (Bax/Bcl-2 and TUNEL positive cells) associated with an increase in CaMKII activity (P-CaMKII and P-Thr17) with respect to aged matched controls. Treatment of SHR for 1 month with enalapril 10mg/kg/day significantly decreases hypertrophy, apoptosis and CaMKII activity. Moreover, after 1 month of acute Iso treatment, Iso-rats also showed an increment in aldosterone serum levels (585.8±29.6%), in blood pressure (29.6±7.3 mm Hg), in heart hypertrophy (LVMI 3.1.8±1.1 mg/mm) and in apoptosis associated with a significant increase in P-CaMKII (99.1±24.2%) and in P-Thr17 (151.3±24.8). The Ca2+ handling, evaluated in isolated myocytes by epifluorescence, was similar among the groups. However, SHR and Iso-rats depicted a significantly increase in ·O2- generation (140.2±29.9 CPM/g) and in TBARS (0.282±0.05 nM/mg prot), with respect to control rats. These results might suggest that endogenous increases in Ang II serum levels could induce apoptosis in vivo associated with a CaMKII activation-dependent pathway. Moreover, the results further show that CaMKII activation was independent on Ca2+ increments and occurred associated with an increase in reactive oxygen species.