Involvement of a p38 mitogen-activated protein kinase phosphatase in protecting neonatal rat cardiac myocytes from ischemia.
Our recent results showed that extended p38 mitogen-activated protein kinase (p38) activation during ischemia leads to cell death, at least partly through apoptosis, in neonatal rat cardiomyocytes. However, other studies have shown that p38 activation during a short preconditioning treatment protects cardiomyocytes from ischemic cell death. This suggests that the duration of p38 activation determines its cellular function and therefore inactivation of p38 by phosphatases may play an important role. In neonatal rat cardiomyocytes, we used the tyrosine phosphatase inhibitor, vanadate, to prevent p38 inactivation, thus extending the strength and length of p38 activation during ischemia. This resulted in higher susceptibility to cell death from ischemia in a dose-dependent manner and over time; the additional damage induced by vanadate was inhibited by SB203580, a selective inhibitor of p38. We conclude that a tyrosine phosphatase is inactivated during ischemia, resulting in prolonged p38 activation which causes cell death.
Mackay
K
K
Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, CA 94305-5332, USA.
Mochly-Rosen
D
D
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007511:Ischemia / Q000378:metabolism* / Q000517:prevention & control*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D014638:Vanadates; D014443:Tyrosine; D007770:L-Lactate Dehydrogenase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580