THE SIGNALING PATHWAY FOR ALDOSTERONE-INDUCED MITOCHONDRIAL PRODUCTION OF SUPEROXIDE ANION IN THE MYOCARDIUM

NOLLY MB (PRIMER AUTOR); CALDIZ CI; YEVES AM; VILLA-ABRILLE MC; MORGAN PE; NICOLAS AMADO MONDACA; ENRIQUE L. PORTIANSKY; CHIAPPE DE CINGOLANI GE; CINGOLANI HE; ENNIS IL

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY

ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2014 vol. 67 p. 60 - 68

0022-2828

Mineralocorticoid receptor (MR) antagonists decrease morbidity and mortality in heart failure patientsfor whom oxidative stress is usual; however, the underlying mechanism for this protection is unclear.Since aldosterone stimulates reactive oxygen species (ROS) production in several tissues, we exploredits effect and the intracellular pathway involved in the rat myocardium. Aldosterone dose-dependentlyincreased O2.- production in myocardial slices. At 10 nmol/L, aldosterone increased O2.- to 165±8.8 %of control, effect prevented not only by the MR antagonists eplerenone and spironolactone (107±7.8and 103±5.3 %, respectively) but also by AG1478 (105±8.0%), antagonist of the EGF receptor (EGFR).Similar results were obtained by silencing MR expression through the direct intramyocardial injectionof a lentivirus coding for a siRNA against the MR. The aldosterone effect on O2.- production wasmimicked by the mKATP channel opener diazoxide and blocked by preventing its opening with 5-HDand glibenclamide, implicating the mitochondria as the source for O2.- . Inhibiting the respiratorychain with rotenone or mitochondrial permeability transition (MPT) with cyclosporine A orbongkrekic acid also cancelled aldosterone-induced O2.- production. In addition, aldosterone effectdepended 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 antagonistshad no effect, suggesting that EGFR transactivation occurred downstream from MR activation.Inhibition of mKATP channels, the respiratory chain, or MPT did not prevent Akt phosphorylation,supporting it happened upstream of the mitochondria. Importantly, cardiomyocytes were confirmed assource of aldosterone induced mitochondrial ROS production in experiments performed in isolatedcardiac myocytes.