The activation of p38 alpha, and not p38 beta, mitogen-activated protein kinase is required for ischemic preconditioning.
Numerous studies show that pharmacological inhibition of p38 mitogen-activated protein kinases (p38s) before lethal ischemia prevents conditioning. However, these inhibitors have off-target effects and do not discriminate between the alpha and beta isoforms; the activation of which is thought to have diverse and perhaps opposing actions with p38 alpha aggravating, and p38 beta reducing, myocardial injury. We adopted a chemical genetic approach using mice in which either the p38 alpha (DR alpha) or p38 beta (DR beta) alleles were targeted to substitute the "gatekeeper" threonine residue for methionine, thereby preventing the binding of a pharmacological inhibitor, SB203580. Isolated, perfused wild-type (WT), DR alpha and DR beta mouse hearts underwent ischemic preconditioning with 4 cycles of 4 min ischemia/6 min reperfusion, with or without SB203580 (10 microM), followed by 30 min of global ischemia and 120 min of reperfusion. In WT and DR beta hearts, SB203580 completely abolished the reduction in myocardial infarction seen with preconditioning and also the phosphorylation of downstream substrates of p38. These effects of SB203580 were not seen in DR alpha hearts. Furthermore ischemic preconditioning occurred unaltered in p38 beta null hearts. Contrary to expectation the activation of p38 alpha, and not p38 beta, is necessary for ischemic preconditioning. Since p38 alpha is also the isoform that leads to lethal myocardial injury, it is unlikely that targeted therapeutic strategies to achieve isoform-selective inhibition will only prevent the harmful consequences of activation.
Sicard
Pierre
P
King's College London BHF Centre, Cardiovascular Division, The Rayne Institute, St. Thomas' Hospital, London SE1 7EH, UK.
Clark
James E
JE
Jacquet
Sebastien
S
Mohammadi
Shahrooz
S
Arthur
J Simon C
JS
O'Keefe
Stephen J
SJ
Marber
Michael S
MS
D000483:Alleles; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D019194:Ischemic Preconditioning; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D048290:Mitogen-Activated Protein Kinase 11 / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism*; D009203:Myocardial Infarction; D010766:Phosphorylation; D020033:Protein Isoforms; D011725:Pyridines / Q000494:pharmacology; D013997:Time Factors
D004791:Enzyme Inhibitors; D007093:Imidazoles; D020033:Protein Isoforms; D011725:Pyridines; D048290:Mitogen-Activated Protein Kinase 11; D048308:Mitogen-Activated Protein Kinase 14; C093642:SB 203580