MEK1/2-ERK1/2 mediates alpha1-adrenergic receptor-stimulated hypertrophy in adult rat ventricular myocytes.

Xiao L, Pimental DR, Amin JK, Singh K, Sawyer DB, Colucci WS
J Mol Cell Cardiol. 2001 33 (4): 779-87

PMID: 11273730 · DOI:10.1006/jmcc.2001.1348

We examined the relative roles of the mitogen-activated protein kinases (MAPK) in mediating the alpha1-adrenergic receptor (alpha1-AR) stimulated hypertrophic phenotype in adult rat ventricular myocytes (ARVM). Norepinephrine (NE; 1 microM) in the presence of the beta -AR antagonist propranolol (Pro; 2 microM) 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, approximately 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 alpha1-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 (as assessed by [3H]leucine incorporation and cellular protein accumulation) and ERK1/2 activation, with approximately 50% inhibition at a concentration between 10 and 50 microM, which is consistent with the known IC50 values of PD98059 for MEK1 (4 microM) and MEK2 (50 microM). Thus, these data show that alpha1-AR stimulated hypertrophy in ARVM is dependent on the MEK1/2-ERK1/2 signaling pathway.

MeSH Terms (27)

Adrenergic alpha-Agonists Adrenergic beta-Antagonists Animals Cardiomegaly Cells, Cultured Enzyme Activation Flavonoids Heart Ventricles JNK Mitogen-Activated Protein Kinases Male MAP Kinase Kinase 1 MAP Kinase Kinase 2 Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Norepinephrine p38 Mitogen-Activated Protein Kinases Prazosin Propranolol Protein-Serine-Threonine Kinases Protein-Tyrosine Kinases Proto-Oncogene Proteins c-raf ras Proteins Rats Rats, Sprague-Dawley Receptors, Adrenergic, alpha-1

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