Abstract 238: Targeted Disruption of the Prostacyclin Receptor Gene Abrogates the Late Phase of Ischemic Preconditioning
Cyclooxygenase-2 is the rate-limiting enzyme in the biosynthesis of prostanoids, such as PGE2 and PGI2, which are increased during late preconditioning (PC). Although the cardioprotection afforded by the late phase of ischemic PC is known to be mediated by cyclooxygenase-2, the role of the prostacyclin receptor (IP) in this phenomenon remains unknown. Accordingly, we tested if targeted disruption of the IP gene abrogates late PC in mice (22 ± 1 wks old) subjected to a 30-min coronary occlusion (O) and 24 h of reperfusion (R). In wild-type (WT) mice (group I, n=17), infarct size averaged 50.7 ± 2.7% of the risk region (Figure⇓). In mice homozygous for a null IP allele (IP−/−, group III, n=12), infarct size was similar (52.9 ± 2.1%), indicating that IP 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 II, n=11), infarct size was reduced to 38.9 ± 2.6%, indicating a late PC effect. In contrast, when IP−/− mice were preconditioned 24 h earlier with six 4-min O/4-min R cycles (group IV, n=12), infarct size was not reduced (52.4 ± 3.7%). We conclude that targeted disruption of the IP gene completely abrogates the infarct-sparing effect of late PC. These studies provide unequivocal molecular genetic evidence for an obligatory role of IP in the cardioprotection afforded by the late ischemic PC.