Regulation of Bcl-2 phosphorylation in response to oxidative stress in cardiac myocytes.
Oxidative stress promotes cardiac myocyte death and has been implicated in the pathogenesis of many cardiovascular diseases. Bcl-2 family proteins are key regulators of the apoptotic response, while their functions can be regulated by post-transcriptional modifications including phosphorylation, dimerization or proteolytic cleavage. This study used adult cardiac myocytes to test the hypothesis that activation of specific kinase signalling pathways by oxidative stress may modulate either the expression or the phosphorylation of Bcl-2, with the resulting effect of a decrease or increase in its anti-apoptotic function. Stimulation of cardiac myocytes with 0.2 mM H(2)O(2), which induces apoptosis, resulted in a marked down-regulation of Bcl-2 protein simultaneously with an increase in its phosphorylation. Inhibition of p38-MAPK resulted in attenuation of Bcl-2 phosphorylation, whereas inhibition of ERK1/2, JNKs or PI-3-K had no effect. These data suggest that activation of p38 MAPK by oxidative stress results in the phosphorylation and degradation of Bcl-2 and the inactivation of its anti-apoptotic activity.
Markou
Thomais
T
Laboratory of Animal Physiology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Dowling
Aileen A
AA
Kelly
Tara
T
Lazou
Antigone
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D007093:Imidazoles; D016877:Oxidants; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D012333:RNA, Messenger; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580