Early response kinase and PI3-kinase activation in adult cardiomyocytes and their role in hypertrophy

The present study investigated the role of early response kinase (ERK) and phosphatidylinositol 3 (PI 3)-kinase in ventricular cardiomyocytes from adu lt rat for the hypertrophic response to alpha-adrenoceptor stimulation. Par ameters of the hypertrophic response were stimulation of protein synthesis and induction of creatine kinase BE. The alpha-adrenoceptor agonist phenyle phrine (10 mu mol/l) activated ERK2 and PI 3-kinase. The protein kinase C i nhibitor bisindolylmaleimide (5 mu mol/l) and the mitogen-activated protein kinase kinase inhibitor PD-98059 (10 mu mol/l) but not the tyrosine kinase inhibitor genistein (100 mu mol/l) blocked ERK2 activation. Inhibition of ERK2 activation abolished induction of creatine kinase BE by phenylephrine but not the increase in protein synthesis. The PI 3-kinase inhibitor wortma nnin (100 nmol/l) blocked protein synthesis under alpha-adrenoceptor stimul ation but did not interfere with ERK2 activation. Inhibition of the ERK2 pa thway with PD-98059 did not affect PI 3-kinase activation. We conclude that ERK2- and PI 3-kinase-dependent pathways represent two mutually exclusive ways of signaling that lead to different aspects of the hypertrophic respon se to alpha-adrenoceptor stimulation.