The tyrosine kinase inhibitor, genistein, prevents alpha-adrenergic-induced cardiac muscle cell hypertrophy by inhibiting activation of the Ras-MAP kinase signaling pathway.
The alpha-adrenergic agonist, phenylephrine, has been widely used to induce hypertrophy in cultured ventricular myocytes from neonatal rats. We have investigated the role of tyrosine phosphorylation in this signaling pathway using the tyrosine kinase inhibitor, genistein. We find that genistein treatment prevents phenylephrine-induced activation of three promoters (Fos, atrial natriuretic factor, ANF, and the myosin light chain 2, MLC-2), which are activated in the hypertrophic response. Genistein also inhibits phenylephrine-induced activation of the mitogen activated protein (MAP) kinases Erk1 and Erk2 and inhibits GTP loading of the Ras protein. These data demonstrate that a genistein-sensitive step is critical for the activation of the Ras-MAP kinase pathway by phenylephrine and suggest that this pathway is important in the regulation of the hypertrophic response.
Thorburn
J
J
Cardiology Division, University of Utah, Salt Lake City 84112.
Thorburn
A
A
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D006332:Cardiomegaly / Q000209:etiology / Q000517:prevention & control*; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D019833:Genistein; D007529:Isoflavones / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1; D009206:Myocardium / Q000201:enzymology*; D009219:Myosin-Light-Chain Kinase / Q000235:genetics; D010656:Phenylephrine / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*
D007529:Isoflavones; D016760:Proto-Oncogene Proteins c-fos; D011942:Receptors, Adrenergic, alpha; D010656:Phenylephrine; D009320:Atrial Natriuretic Factor; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D009219:Myosin-Light-Chain Kinase; D019950:Mitogen-Activated Protein Kinase 1