Stress-activated protein kinase phosphorylation during cardioprotection in the ischemic myocardium.
Stress-activated protein kinases may be essential to cardioprotection. We assessed the role of p38 in an in vivo rat model of ischemia-reperfusion. Ischemic preconditioning (IPC) and the delta(1)-opioid receptor agonist 2-methyl-4aalpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aalpha-octahydroquinolino [2,3,3-g]isoquinoline (TAN-67) significantly reduced infarct size (IS), expressed as a percentage of the area at risk (AAR), versus animals subjected only to 30 min of ischemia and 2 h of reperfusion (7.1 +/- 1.5 and 29.6 +/- 3.3 vs. 59.7 +/- 1.6%). The p38 antagonist SB-203580 attenuated IPC when it was administered before (34.0 +/- 6.9%) or after (25.0 +/- 3.8%) the IPC stimulus; however, it did not significantly attenuate TAN-67-induced cardioprotection (39.6 +/- 3.2). We also assessed the phosphorylation of p38 and c-jun NH(2)-terminal kinase (JNK) throughout ischemia-reperfusion in nuclear and cytosolic fractions. After either intervention, no increase was detected in the phosphorylation state of either enzyme in the nuclear fraction or for p38 in the cytosolic fraction versus control hearts. However, there was a robust increase in JNK activity in the cytosolic fraction immediately on reperfusion that was more pronounced in animals subjected to IPC or administered TAN-67. These data suggest that SB-203580 likely attenuates IPC via the inhibition of kinases other than p38, which may include JNK. The data also suggest that activation of JNK during early reperfusion may be an important component of cardioprotection.
Fryer
R M
RM
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Patel
H H
HH
Hsu
A K
AK
Gross
G J
GJ
D000818:Animals; D003331:Coronary Vessels / Q000503:physiopathology / Q000601:surgery; D019610:Cytoprotection / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000819:agonists; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D011804:Quinolines; D017465:Receptors, Opioid, delta; C094142:TAN 67; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580