Cardiac overexpression of a Gq inhibitor blocks induction of extracellular signal-regulated kinase and cJun NH2-terminal kinase activity in in vivo pressure overload

Background-Understanding the cellular signals that initiate cardiac hypertrophy is of critical importance in identifying the pathways that mediate heart failure. The family of mitogen-activated protein kinases (MAPKs), including the extracellular signal-regulated kinases (ERKs), c-Jun NH2-terminal kinase (JNK), and p38 MAPKs, may play specific roles in myocardial growth and function. Methods and Results-To determine the mechanism of activation of MAPK pathways during the development of cardiac hypertrophy, we evaluated the induction of MAPK activity after aortic constriction in wild-type and in 2 types of cardiac gene-targeted mice: one overexpressing a carboxyl-terminal peptide of G(alphaq) that inhibits G(q)-mediated signaling (TC GqI mouse) and another overexpressing a carboxyl-terminal peptide of beta-adrenergic receptor kinase-l that inhibits G beta gamma signaling (TG beta ARKct mouse). Wild-type mice with pressure overload showed an acute induction of NK, followed by the induction of p38/p38 beta at 3 days and ERK at 7 days. Both JNK and p38 activity remained elevated at 7 days after banding. In TG GqI mice, hypertrophy was significantly attenuated, and induction of ERK and JNK activity was abolished, whereas the induction of p38 and p38 beta was robust, but delayed, By contrast, all 3 MAPK pathways were activated by aortic constriction in the TG beta ARKct hearts, suggesting a role for G(alphaq), but not G beta gamma. Conclusions-Taken together, these data show that the induction of ERK and JNK activity in in vivo pressure-overload hypertrophy is mediated through the stimulation of G(q)-coupled receptors and that non-G(q)-mediated pathways are recruited to activate p38 and p38 beta.