Abstract 3304: The Cardioprotective Effect of Prostaglandin E2/EP4 System is Important for the Late Phase Preconditioning
Background: Late phase ischemic preconditioning (L-IPC) is a phenomenon that after 1 days of a brief ischemia of the heart induces a potent cardioprotective mechanism. Expression of COX-2, the rate-limiting enzyme for the synthesis of prostanoids is upregulated in the heart in response to ischemia and contributes to L-IPC. However, their mechanisms are still unclear.
Purpose: To test if PGE2-EP4 system is crucial signal for L-IPC, we examined mice lacking PGE2 receptor EP4 (EP4−/− mice) under an IPC model.
Methods: Ischemic/reperfusion (I/R) was induced by 30 min of left anterior descending artery (LAD) occlusion followed by reperfusion for indicated times, and cardiac infarction size (CIS) was estimated by TTC staining. Prior I/R, Wild-type (WT) and EP4−/− mice were subjected to IPC treatment: 4 cycles of 5 min occlusion and reperfusion LAD. Sham group was undergone the same surgery except IPC treatment.
Results: The expression of COX-2 was significantly induced in the heart at 6 hours, and accordingly the level of cardiac PGE2 was increased at 24 hours after cardiac ischemia, but the level of PGE2 was not different between WT and EP4−/− mice. Consist with the time-course of COX-2/PGE2 levels, I/R-induced CIS was increased in EP4−/− compared to WT after 24 hours by 35.7%, but not different at 2 hours of I/R among WT and EP4−/− mice (p<0.05, n=10). However, at 24 hours of IPC-treatment, in which cardiac PGE2 was significantly increased, CIS was decreased in WT by 44.1%, but not EP4−/− even after 2 hours of I/R (n=4, p<0.05). When ONO-AE1–329, EP4 agonist were applied 30 min before I/R, CIS was decreased in WT, but not EP4−/−. ONO-AE1–329 enhanced the I/R-induced Akt activation, an anti-apoptotic signal-molecule in WT by 59.1%, but not in EP4−/− heart (n=3, p<0.05).
Conclusion: The PGE2-EP4 system in the heart plays a critical role in late phase IPC, and upregulation of I/R-induced Akt activity would participate in cardioprotective effects of PGE2/EP4.