Endogenous endothelin 1 mediates angiotensin II-induced hypertrophy in electrically paced cardiac myocytes through EGFR transactivation, reactive oxygen speciesand NHE-1.

CORREA MV; NOLLY MB; CALDIZ CI; CHIAPPE DE CINGOLANI GE; CINGOLANI HE; ENNIS IL

PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY

SPRINGER

Lugar: Berlin; Año: 2014 p. 1819 - 1830

0031-6768

Emerging evidence supports a key role for endothelin-1 (ET-1) and the transactivation of the epidermal growth factor receptor (EGFR) in Angiotensin II (Ang II) action. We aim to determine the potential role played by endogenous ET-1, EGFR transactivation and redox-dependent sodium hydrogen exchanger-1 (NHE-1) activation in the hypertrophic response to Ang II of cardiac myocytes. Electrically paced adult cat cardiomyocytes were placed in culture and stimulated with 1 nmol L-1 Ang II or 5 nmol L-1 ET-1. Ang II increased ~45 % cell surface area and ~37 % [3H]-phenylalanine incorporation, effects that were blocked not only by losartan (Los) but also by BQ123 (AT1 and ETA receptor antagonist, respectively). Moreover, Ang II significantly increased ET-1 mRNA expression. ET-1 similarly increased myocyte cell surface area and protein synthesis, actions prevented by the reactive oxygen species scavenger MPG or the NHE-1 inhibitor cariporide (carip). ET-1 increased the phosphorylation of the redox-sensitive ERK1/2-p90RSK kinases, main activators of the NHE-1. This effect was prevented by MPG and the antagonist of EGFR, AG1478. Ang II, ET-1 and EGF increased myocardial superoxide production (187± 9, 149±8 and 163.7±6 % of control, respectively) and AG1478 inhibited these effects. Interestingly, Los inhibited only Ang II while BQ123 cancelled both Ang II and ET-1 actions, supporting the sequential and unidirectional activation of AT1, ETA and EGFR. Based on the present evidence, we propose that endogenous ET-1 mediates the hypertrophic response to Ang II by a mechanism that involves EGFR transactivation and redox-dependent activation of the ERK1/2-p90RSK and NHE-1 in adult cardiomyocytes.