The slow force response to myocardial stretch requires transactivation of the epidermal growth factor receptor

NÉSTOR G. PÉREZ; CLAUDIA I. CALDIZ; GLADYS CHIAPPE DE CINGOLANI; HORACIO E. CINGOLANI

Orlando, Florida, USA

Congreso; Scientific Sessions of The American Heart Association; 2009

American Heart Association

Mechanical stretch is an important physiological and pathological stimulus to the heart. Stretch elicits a biphasic contractile response: The Frank-Starling mechanism, followed by a slower increase in developed force called slow force response (SFR) or Anrep effect. The fact that the SFR is blunted by AT1 or ETA receptors blockade as well as by NHE-1 inhibition and reactive oxygen species scavenging, suggests that it is the mechanical counterpart of an autocrine/paracrine mechanism involving the release of preformed angiotensin II (AngII) and endothelin (ET) what leads to a redox sensitive activation of the NHE-1. Since recent evidence indicates that AngII/ET exert their effect through transactivation of the epidermal growth factor receptor (EGFR) we hypothesized that the chain of events leading to the SFR would be blunted by avoiding EGFR activation by AG1478. Isolated cat papillary muscles were stretched from 92 to 98 % of Lmax. The SFR was 123±1 % of the initial rapid phase (n=6, P<0.05 vs rapid phase) and was blunted by EGFR inhibition with AG1478 (1 µmol/L) (98±2 %, n=6, P<0.05 vs SFR), clearly involving transactivation of the EGFR in its development. Since we have previously demonstrated that the chain of events leading to the SFR depend on the activation of kinases upstream NHE-1 and that those kinases are activated through mitochondrial reactive oxygen species, superoxide anion production induced by AngII and ET-1 was assessed (lucigenin method) with and without inhibition of the EGFR. Both AngII (1 nmol/L) and ET-1 (5 nmol/L) induced an increase in superoxide anion production that reached 146±14 (n=9) and 191±17 (n=13) % of control, respectively (P<0.05), effects that were both suppressed by EGFR blockade [94±5 (n=12) and 98±15 (n=8) % of control, respectively]. In addition of being consistent with previously reported results on the SFR, these data shows for the first time that EGFR transactivation is a necessary step in the chain of events leading to the Anrep effect.