Abstract
Background Lipocalin-type prostaglandin D synthase (L-PGDS) is abundantly expressed in adult cardiomyocytes. We recently demonstrated that dexamethasone stimulates PGD2-dominated activation of prostanoid biosynthesis via induction of phospholipase A2 and cyclooxygenase-2, thereby protecting hearts against ischemia/reperfusion injury. Here, we examined the downstream signaling responsible for cardioprotection mediated through PGD2-dominated activation of prostanoid biosynthesis. Methods and Results (1) In cultured neonatal rat cardiomyocytes, PGD2 strongly activated ERK in a dose-dependent manner, although canonical PGD2 receptors, including DP (PGD2 receptor) and CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) receptors, were hardly expressed on cardiomyocytes. (2) Interestingly, PGD2 bound to FP receptor (the canonical PGF2α receptor) with an affinity comparable to that for the DP receptor, and the FP receptor was abundantly expressed in cardiomyocytes. (3) PGD2-induced ERK activation was completely blocked by FP antagonist or siRNA-mediated knockdown of the FP, but not by DP and CRTH2 antagonist and siRNA-mediated knockdown of DP and CRTH2. (4) PGD2 activated ERK in Langendorff perfused DP-knock-out (KO) and CRTH2-KO mice hearts to comparable levels as those observed for wild-type hearts, while it did not activate ERK in FP-KO hearts. (5) Dexamethasone protected hearts against ischemia-reperfusion injury in L-PGDS-dependent manner. The dexamethasone-mediated cardioprotection was partially cancelled in FP-KO mice. (6) Gene-chip and Q-PCR analysis revealed that dexamethasone induced Nrf2-dependent antioxidant gene expression in wild-type mice, but not in L-PGDS KO mice. Dexamethasone-mediated cardioprotection against ischemia-reperfusion injury was partially attenuated in Nrf-2 KO mice. (7) In cultured cardiomyocytes, PGD2 had little effect on Nrf2 activation, while 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), which is formed from PGD2, strongly activated Nrf2. Conclusion PGD2 and 15d-PGJ2 are cooperatively involved in the L-PGDS-mediated cardioprotection against ischemia-reperfusion injury via FP receptor and Nrf-2 activation, respectively.
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