THE TYROSINE KINASE INHIBITOR, GENISTEIN, PREVENTS ALPHA-ADRENERGIC-INDUCED CARDIAC-MUSCLE CELL HYPERTROPHY BY INHIBITING ACTIVATION OF THERAS-MAP KINASE SIGNALING PATHWAY

The alpha-adrenergic agonist, phenylephrine, has been widely used to i nduce hypertrophy in cultured ventricular myocytes from neonatal rats. We have investigated the role of tyrosine phosphorylation in this sig naling 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 respons e. Genistein also inhibits phenylephrine-induced activation of the mit ogen activated protein (MAP) kinases Erk1 and Erk2 and inhibits GTP lo ading of the Ras protein. These data demonstrate that a genistein-sens itive step is critical for the activation of the Ras-MAP kinase pathwa y by phenylephrine and suggest that this pathway is important in the r egulation of the hypertrophic response. (C) 1994 Academic Press, Inc.