|Sumario:||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 ET1. Ang II increased ~45 % cell surface area (CSA) and ~37 % [³H]-phenylalanine incorporation, effects that were blocked not only by losartan (Los) but also by BQ123 (AT₁ and ET<sub>A</sub> receptor antagonists, respectively). Moreover, Ang II significantly increased ET-1 messenger RNA (mRNA) expression.
ET-1 similarly increased myocyte CSA 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- p90<sup>RSK</sup> 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 whilst BQ123 cancelled both Ang II and ET-1 actions, supporting the sequential and unidirectional activation of AT₁, ET<sub>A</sub> 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-p90<sup>RSK</sup> and NHE-1 in adult cardiomyocytes.|