Abstract 354: Prostaglandin D2-F Type Prostanoid Receptor Signaling Is a Novel Cardiomyocyte Survival Pathway
Background: Lipocalin-type prostaglandin D synthase (L-PGDS) is abundantly expressed on cardiomyocytes. We recently demonstrated that dexamethasone stimulates PGD2-dominated activation of prostanoid biosynthesis, thereby protecting hearts against ischemia/reperfusion injury. Here, we examined the downstream signaling responsible for cardioprotection mediated through PGD2-dominated activation.
Methods and Results: (1) In cultured neonatal rat cardiomyocytes, PGD2 strongly activates 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, are hardly expressed on cardiomyocytes. (2) Interestingly, PGD2 bounds to FP receptor (the canonical PGF2α receptor) with an affinity comparable to that for the DP receptor, and the FP receptor is abundantly expressed on cardiomyocytes. (3) PGD2-induced ERK activation is 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 activates ERK in Langendorff perfused DP-knock out (KO) and CRTH2-KO mice hearts to comparable levels as those observed for wild-type hearts, while cannot activate it in FP-KO hearts. (5) Consistently, the cardioprotective effect of PGD2-dominated activation by dexamethasone was blunted in FP KO hearts. (6) Furtermore, genomewide gene expression profiles by microarray analysis and quantitative real-time RT-PCR analysis identified that Nrf-2 was the downstream target of L-PGDS-mediated PGD2 biosynthesis. (7) In cultured cardiomyocytes, FP agonist stimulated Nrf2 nuclear translocation and consequently induced Nrf2-target genes expression in an ERK-dependent manner. (8) Finally, The cardioprotective effect by dexamethasone was completely abolished in Nrf-2 KO hearts.
Conclusion: FP serves as a functionally relevant PGD2 receptor in the hearts and PGD2-FP signaling plays a substantial role in the improvement of functional recovery after ischemia-reperfusion injury in the heart. Nrf-2 is a major effector molecule responsible for the cardioprotecton elicited by L-PGDS-derived PGD2.
- © 2012 by American Heart Association, Inc.