Regulation of MAPK and PI‐3K by Bradykinin and Angiotensin II during Eccentric Cardiac Hypertrohy

Abstract

Bradykinin (BK) and angiotensin II (ANG II) improve myocardial contractility. While ANG II induces cardiac hypertrophy through activation of MAPK and PI-3K, BK plays a major role in its regression. The purpose of this study was to elucidate the role of MAPK and PI-3K in the transduction of BK and ANG II signaling during the development of eccentric cardiac hypertrophy, induced by aorto-caval shunt in adult rats. Hearts were retrogradely superfused (20 min) with either Tyrode alone, or with ANG II (10−7M) or BK (10−6M). Activation of ERK1/2, p38 and Akt were assessed by western blot analysis for the relative level of phosphorylation versus total protein. As compared to sham, hypertrophied hearts showed higher activation of ERK1 (56%), ERK2 (227%), p38 (75%) and Akt (67%). In normal hearts, ANG II did not affect Akt activity but increased that of ERK1, ERK2 and p38 by 57%, 196%, 94%, respectively. However, ANG II had no major effect in the hypertrophied hearts. On the other hand, BK induced a minor activation of ERK1 (27%), ERK2 (31%), p38 (29%) and Akt (11%), in the normal hearts. However in the hypertrophied hearts, BK activation induced activation of ERK2 (42%) and p38 (57%). Thus, eccentric cardiac hypertrophy is associated with dysfunctional ANG II-MAPK activation but an enhanced BK-induced one. Supported in part by grants GM08016-38 NIGMS/NIH and 2G12 RR003048 RCMI, Division of Research Infrastructure, NCRR/NIH.