Early response kinase and PI 3-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 adult rat for the hypertrophic response to alpha-adrenoceptor stimulation. Parameters of the hypertrophic response were stimulation of protein synthesis and induction of creatine kinase BB. The alpha-adrenoceptor agonist phenylephrine (10 micromol/l) activated ERK2 and PI 3-kinase. The protein kinase C inhibitor bisindolylmaleimide (5 micromol/l) and the mitogen-activated protein kinase kinase inhibitor PD-98059 (10 micromol/l) but not the tyrosine kinase inhibitor genistein (100 micromol/l) blocked ERK2 activation. Inhibition of ERK2 activation abolished induction of creatine kinase BB by phenylephrine but not the increase in protein synthesis. The PI 3-kinase inhibitor wortmannin (100 nmol/l) blocked protein synthesis under alpha-adrenoceptor stimulation but did not interfere with ERK2 activation. Inhibition of the ERK2 pathway 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 response to alpha-adrenoceptor stimulation.
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002250:Carbon Radioisotopes; D002273:Carcinogens / Q000494:pharmacology; D006332:Cardiomegaly / Q000201:enzymology*; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D003402:Creatine Kinase / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006352:Heart Ventricles / Q000166:cytology / Q000201:enzymology; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D009025:Morpholines / Q000494:pharmacology; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D009206:Myocardium / Q000737:chemistry / Q000166:cytology / Q000201:enzymology*; D010656:Phenylephrine / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D000077191:Wortmannin