The Signaling Pathway for Aldosterone-induced Mitochondrial Production of Superoxide Anion in the Myocardium

IRENE L ENNIS; CLAUDIA CALDIZ; MARIA C VILLA-ABRILLE; PATRICIO E MORGAN; GLADYS E CHIAPPE DE CINGOLANI; HORACIO E CINGOLANI

Los Angeles

Congreso; Scientific Sessions 2012; 2012

American heart Association

Mineralocorticoid receptor (MR) antagonists decrease morbidity and mortality in heart failure patients for whom oxidative stress is common; however, the underlying mechanism of MR-antagonist protection is unclear. Because aldosterone stimulates reactive oxygen species production, we explored in rat myocardium the effect of aldosterone on O2- production and the intracellular pathway involved. Aldosterone dose-dependently stimulated O2- production. At 10 nmol/L, aldosterone increased O2- to 165±8.8 % of control, an effect prevented by the MR antagonists, eplerenone and spironolactone (107±7.8 and 103±5.3 %, respectively), and by inhibition of EGF receptor (EGFR) with AG1478 (105±8.0%), implicating EGFR transactivation in this pathway. Similar results were obtained silencing MR expression by direct intramyocardial injection of a lentivirus coding for a siRNA against the MR. The aldosterone effect was mimicked by the mKATP channel opener diazoxide but blocked by preventing its opening with 5-HD and glibenclamide, implicating the mitochondria as the O2- source. Inhibiting the respiratory chain with rotenone also cancelled aldosterone-induced O2- production. In addition, the aldosterone effect depended on NADPH oxidase and phosphoinositide 3-kinase activation, as apocynin and wortmannin respectively inhibited it. EGF (0.1µg/mL) similarly increased O2-, although in this case MR antagonists had no effect, suggesting that EGFR transactivation occurred downstream from MR. The results allow us to propose that a decrease in oxidative stress may be one of the mechanisms contributing to the beneficial effects of MR antagonists in heart failure.