p38 mitogen-activated protein kinase (MAPK) is activated by noradrenaline and serves a cardioprotective role, whereas adrenaline induces p38 MAPK dephosphorylation.
1. The aim of the present study was to investigate the role of p38 mitogen-activated protein kinases (MAPK) in mediating the effect of noradrenaline (NA) on cardiomyocyte cell viability. 2. Cardiomyocytes from embryonic chick heart were treated with various concentrations of NA, phenylephrine or isoproterenol and p38 MAPK activation was determined by western blotting. Total cell death was assessed by the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Apoptosis was determined by specific DNA fragmentation. 3. At 100 micromol/L, NA produced a significant increase in cell death that was associated with microscopic changes and DNA fragmentation indicative of apoptosis. The p38 MAPK inhibitor SB202190 (at 1 micromol/L beginning 1 h before NA), reduced NA-induced p38 MAPK activation and significantly accentuated NA-induced cell death. In contrast, the mitogen-activated protein kinase kinase ERK1/2 inhibitor PD98059 (at 1 micromol/L beginning 1 h before NA) did not significantly alter NA-induced cell death. These effects of NA were mediated, in part, through alpha-adrenoceptor because phenylephrine (100 micromol/L), like NA, also induced p38 MAPK activation. However, 100 micromol/L isoproterenol produced a sustained dephosphorylation of p38 MAPK. 4. These data show that NA-induced p38 MAPK activation, through alpha-adrenoceptor, has a protective role in cardiomyocytes to antagonize NA-induced cell death. In contrast, beta-adrenoceptor stimulation produces dephosphorylation of p38 MAPK.
University of British Columbia, Department of Medicine (Cardiology), Vancouver, British Columbia, Canada.
Michael Yc
MY
Tsang
Simon W
SW
Rabkin
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004837:Epinephrine / Q000737:chemistry / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D009638:Norepinephrine / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D002316:Cardiotonic Agents; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D009638:Norepinephrine; D004837:Epinephrine