Aldosterone stimulates the cardiac Na+/H+ exchanger via transactivation of the epidermal growth factor receptor.

DE GIUSTI VC; NOLLY MB; YEVES AM; CALDIZ CI; VILLA ABRILLE MC; CHIAPPE DE CINGOLANI GE; ENNIS IL; CINGOLANI HE; AIELLO EA

Orlando, FL

Congreso; High Blood Pressure Research Council of the American Heart Association; 2011

American Heart Association

The use of antagonists of the mineralocorticoid receptor (MR) in the treatment of myocardial hypertrophy and heart failure has gained increasing importance in the last years. The up-regulation of the activity of the cardiac Na+/H+ exchanger (NHE-1) induced by aldosterone could account for the genesis of these pathologies. We tested whether aldosterone-induced NHE-1 stimulation involves the transactivation of the epidermal growth factor receptor (EGFR). Rat ventricular myocytes were used to measure intracellular pH with epifluorescence. pH data are presented as proton flux difference (DJH, mmol/L/min) between control and treatment at pHi 6.8 (* indicates p<0.05). Aldosterone (10 nmol/L) enhanced the NHE-1 activity (0.88±0.2*, n=5). This effect was canceled by the MR antagonists spironolactone (-0.21±0.33, n=5) or eplerenone (-0.25±0.32, n=6), but not by the glucocorticoid receptor antagonist mifepristone (0.82±0.23*, n=4) or the protein synthesis inhibitor cycloheximide (0.95±0.24*, n=5), indicating that the mechanism is mediated by non-genomic pathways triggered by the MR. Aldosterone-induced NHE-1 stimulation was abolished by the EGFR kinase inhibitor AG1478 (-0.29±0.08) and by MMPI (0.02±0.36, n=7), the inhibitor of the metalloproteinases that release EGF from the cell, suggesting that this effect is mediated by transactivation of EGFR. Aldosterone-induced NHE-1 stimulation was associated to the increase in the phosphorylation level of the kinase p90RSK and NHE-1 serine703, effects that were blocked by AG1478 and MMPI. Exogenous EGF (1 mg/mL) mimicked the effects of aldosterone on NHE-1 activity (0.95±0.34*, n=5). Aldosterone and EGF were also able to increase reactive oxygen species (ROS) production. Consistently, the EGF-induced activation of the NHE-1 was abrogated by the ROS scavenger MPG (-42±0.18, n=4), indicating that ROS are participating as signaling molecules. We present for the first time that aldosterone enhances the cardiac NHE-1 activity via transactivation of the EGFR, formation of ROS and phosphorylation of the exchanger. These results call the attention about the consideration of the EGFR as a new potential therapeutic target of the cardiovascular pathologies involving the participation of aldosterone.