Targeted disruption of cox-2 gene abrogates the late phase of ischemic preconditioning

Abstract

Pharmacologic studies with selective cyclooxygenase-2 (COX-2) inhibitors suggest that the late phase of ischemic preconditioning (PC) is mediated by inducible COX (COX-2). However, nonspecific effects of COX-2 inhibitors cannot be ruled out, and the selectivity of these inhibitors for COX-2 vs. COX-1 is only relative. Accordingly, we tested if targeted disruption of the COX-2 gene abrogates late PC in mice subjected to a 30-min coronary occlusion (O) and 24 h of reperfusion (R). In wild-type (WT) mice (group I), infarct size averaged 59.5±2.8% of the risk region (Figure). In mice homozygous for a null COX-2 allele (COX-2 knockout [KO], group II), infarct size was similar (62.0±2.2%), indicating that COX-2 does not modulate infarct size in the absence of PC. When WT mice were preconditioned 24 h earlier with six 4 min O/4-min R cycles (group V), infarct size was markedly reduced to 34.0±3.7%, indicating a late PC effect. In contrast, when COX-2 KO mice were preconditioned 24 h earlier with six 4-min O/4-min R cycles (group VI), infarct size was not reduced (59.8±3.0%). In conclusion, targeted disruption of the COX-2 gene completely abrogates the infarct-sparing effect of late PC, providing unequivocal molecular genetic evidence for an obligatory role of COX-2 in the cardioprotection afforded by the late phase of ischemic PC.