MEK1/2-ERK1/2 mediates α1-adrenergic receptor-stimulated hypertrophy in adult rat ventricular myocytes

We examined the relative roles of the mitogen-activated protein kinases (MAPK) in mediating the alpha (1)-adrenergic receptor (alpha (1)-AR) stimulated hypertrophic phenotype in adult rat Ventricular myocytes (ARVM). Norepinepkrine (NE; 1 muM) in the presence of the beta -AR antagonist propranolol (Pro: 2 muM) caused activation of Ras (>six-fold), MAPK/ERK kinase 1 and 2 (MEK1/2, >10-fold) and extracellular signal regulated kinases 1 and 2 (ERK1/2, similar to 30-fold) within 5 min, as determined by kinase activity assays and Western blots using phospho-specific antibodies. Conversely, p38 and c-Jun amino-terminal kinases (JNK) were not activated by NE/Pro, Activated MEK1/2 signals remained detectable at 2 h, and activated ERI(1/2 remained detectable at 48 h, The alpha (1)-AR selective inhibitor prazosin (100 nM) completely inhibited the NE/Pro-stimulated activation of Ras, MEK1/2: and ERK1/2, The MEK inhibitor PD98059 caused a concentration-dependent inhibition of NE/Pro-stimulated protein synthesis las assessed by [H-3]leucine incorporation and cellular protein accumulation) and ERK1/2 activation, with similar to 50% inhibition at a concentration between 10 and 50 muM, which is consistent with the known IC50 values of PD98059 for MEK1 (4 muM) and MEK2 (50 muM). Thus, these data show that alpha (1)-AR stimulated hypertrophy in ARVM is dependent on the MEK1/2-ERK1/2 signaling pathway. (C) 2001 Academic Press.