Cardiac overexpression of a G(q) inhibitor blocks induction of extracellular signal-regulated kinase and cJun NH2-terminal kinase activity in in vivopressure overload

Background-Understanding the cellular signals that initiate cardiac hypertr ophy is of critical importance in identifying the pathways that mediate hea rt failure. The family of mitogen-activated protein kinases (MAPKs), includ ing the extracellular signal-regulated kinases (ERKs), c-Jun NH2-terminal k inase (JNK), and p38 MAPKs, may play specific roles in myocardial growth an d function. Methods and Results-To determine the mechanism of activation of MAPK pathwa ys during the development of cardiac hypertrophy, we evaluated the inductio n 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 anot her overexpressing a carboxyl-terminal peptide of P-adrenergic receptor kin ase-l that inhibits G betay signaling (TG beta ARKct mouse). Wild-type mice with pressure overload showed an acute induction of NK, followed by the in duction of p38/p38 beta at 3 days and ERK at 7 days. Both JNK and p38 activ ity remained elevated at 7 days after banding. In TG GqI mice, hypertrophy was significantly attenuated, and induction of ERK and JNK activity was abo lished, whereas the induction of p38 and p38 beta was robust, but delayed, By contrast, all 3 MAPK pathways were activated by aortic constriction in t he TG beta ARKct hearts, suggesting a role for G(alphaq), but not G betay. Conclusions-Taken together, these data show that the induction of ERK and J NK activity in in vivo pressure-overload hypertrophy is mediated through th e stimulation of G(q)-coupled receptors and that non-G,-mediated pathways a re recruited to activate p38 and p38 beta.