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 theα1 -adrenergic receptor (α1-AR) stimulated hypertrophic phenotype in adult rat ventricular myocytes (ARVM). Norepinephrine (NE; 1 μ ) in the presence of the β -AR antagonist propranolol (Pro; 2 μ ) 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, 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 ERK1/2 remained detectable at 48 h. The α1-AR selective inhibitor prazosin (100 n ) 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 (as assessed by [3H]leucine incorporation and cellular protein accumulation) and ERK1/2 activation, with ~50% inhibition at a concentration between 10 and 50μ M , which is consistent with the known IC50values of PD98059 for MEK1 (4 μ M) and MEK2 (50 μ M ). Thus, these data show that α1-AR stimulated hypertrophy in ARVM is dependent on the MEK1/2–ERK1/2 signaling pathway.