Stress-activated protein kinase phosphorylation during cardioprotection inthe ischemic myocardium

Stress-activated protein kinases may be essential to cardioprotection. We a ssessed the role of p38 in an in vivo rat model of ischemia-reperfusion. Is chemic preconditioning (IPC) and the delta (1)-opioid receptor agonist 2-me thyl-4a alpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a alpha -octahydroquinoli no [2,3,3-g]isoquinoline (TAN-67) significantly reduced infarct size (IS), expressed as a percentage of the area at risk (AAR), versus animals subject ed 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 whe n it was administered before (34.0 +/- 6.9%) or after (25.0 +/- 3.8%) the I PC stimulus; however, it did not significantly attenuate TAN-67-induced car dioprotection (39.6 +/- 3.2). We also assessed the phosphorylation of p38 a nd c-jun NH2-terminal kinase (JNK) throughout ischemia-reperfusion in nucle ar and cytosolic fractions. After either intervention, no increase was dete cted 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 adm inistered TAN-67. These data suggest that SB-203580 likely attenuates IPC v ia the inhibition of kinases other than p38, which may include JNK. The dat a also suggest that activation of JNK during early reperfusion may be an im portant component of cardioprotection.