Antiischemic effects of SB203580 are mediated through the inhibition of p38alpha mitogen-activated protein kinase: Evidence from ectopic expression of an inhibition-resistant kinase.
The aim of the present study was to determine whether the attenuation of myocardial ischemic injury by SB203580 is due to the inhibition of p38 mitogen-activated protein kinase (MAPK) or to other documented nonspecific effects of the drug. We made adenoviral vectors encoding the alpha isoform of p38 MAPK with or without site-directed mutations to prevent SB203580 binding and inhibition. In embryonal rat heart-derived cells and adult rat cardiocytes expressing wild-type p38alpha MAPK, injury was reduced significantly by SB203580 present during simulated ischemia. In contrast, SB203580 did not protect cells expressing the SB203580-resistant form of p38alpha MAPK. These observations suggest that SB203580-mediated protection depends on the inhibition of p38alpha MAPK.
Martin
J L
JL
Department of Cardiology, King's College London, The Rayne Institute, St Thomas' Hospital, London.
Avkiran
M
M
Quinlan
R A
RA
Cohen
P
P
Marber
M S
MS
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004351:Drug Resistance / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000201:enzymology; D009206:Myocardium / Q000166:cytology / Q000201:enzymology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D015427:Reperfusion Injury / Q000201:enzymology / Q000517:prevention & control*; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580