p38 mitogen-activated protein kinase pathway protects adult rat ventricular myocytes against beta -adrenergic receptor-stimulated apoptosis. Evidence for Gi-dependent activation.
We have shown that stimulation of beta-adrenergic receptors (beta-AR) by norepinephrine (NE) increases apoptosis in adult rat ventricular myocytes (ARVMs) via a cAMP-dependent mechanism that is antagonized by activation of G(i) protein. The family of mitogen-activated protein kinases (MAPKs) is involved in the regulation of cardiac myocyte growth and apoptosis. Here we show that beta-AR stimulation activates p38 kinase, c-jun N-terminal kinases (JNKs), and extracellular signal-regulated kinase (ERK1/2) in ARVMs. Inhibition of p38 kinase with SB-202190 (10 micrometer) potentiated beta-AR-stimulated apoptosis as measured by flow cytometry and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) staining. SB-202190 at this concentration specifically blocked beta-AR-stimulated activation of p38 kinase and its downstream substrate MAPK-activated protein kinase-2 (MAPKAPK2). Pertussis toxin, an inhibitor of G(i)/G(o) proteins, blocked the activation of p38 kinase and potentiated beta-AR-stimulated apoptosis. Activation of G(i) protein with the muscarinic receptor agonist carbachol protected against beta-AR-stimulated apoptosis. Carbachol also activated p38 kinase, and the protective effect of carbachol was abolished by SB-202190. PD-98059 (10 micrometer), an inhibitor of ERK1/2 pathway, blocked beta-AR-stimulated activation of ERK1/2 but had no effect on apoptosis. These data suggest that 1) beta-AR stimulation activates p38 kinase, JNKs, and ERK1/2; 2) activation of p38 kinase plays a protective role in beta-AR-stimulated apoptosis in cardiac myocytes; and 3) the protective effects of G(i) are mediated via the activation of p38 kinase.
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Myocardial Biology Unit and Cardiovascular Division, Boston University Medical Center, Boston Veterans Affairs Medical Center and Boston University School of Medicine, Massachusetts 02118, USA.
Colucci
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WS
Singh
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D000818:Animals; D017209:Apoptosis; D004789:Enzyme Activation; D016193:G1 Phase; D006352:Heart Ventricles / Q000166:cytology* / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D011943:Receptors, Adrenergic, beta; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases