Abstract 15686: PGD2 Protects Cardiomyocytes Against Ischemia Reperfusion Injury via the FP Receptor, but Not the Canonical PGD2 Receptor
Background: We recently demonstrated that PGD2-dominated activation of prostanoid biosynthesis by selective activation of the glucocorticoid receptor protects cardiomyocytes against ischemia-reperfusion injury (J Clin Invest 2009). Two distinct G-protein coupled receptors, the DP receptor and the CRTH2 receptor, have been identified as PGD2 receptors. However, there is little expression of canonical PGD2 receptors, DP and CRTH2, on cardiomyocytes. We investigated the mechanisms underlying cardioprotection afforded by PGD2.
Methods and Results:(1) In cultured neonatal rat cardiomyocytes, PGD2 selective activates ERK in a dose-dependent manner, with a significant response from 1 nM, reaching maximal activation at 100 nM. Activation of ERK occurred within 1 min, peaked at 3 min, and continued as long as 6 hours. (2) PGD2 protects cardiomyocytes from cell death induced by anoxia-reoxygenation. The MEK inhibitor significantly abrogates the cardioprotective effect of PGD2. (3) Neither DP-agonist (BW245c) nor CRTH2-agonist (13, 14_dihydro_15_keto PGD2) can stimulate ERK in cardiomyocytes. Consistently, neither DP-antagonist (BWA868c), CRTH2-antagonist (CAY10471), nor combination of two can block PGD2-mediated ERK activation. (4) PGD2 bounds to the mouse FP receptor (a canonical PGF2 receptor) with an affinity comparable to that for the mouse DP receptor and the FP receptor is abundantly expressed in rat cardiomyocytes. Consistent with these observations, PGD2-induced ERK activation is completely blocked by FP-antagonist (AL8810) or siRNA-mediated knockdown of the FP receptor. (5) In the Langendorff model, PGD2 activated ERK in DP knockout (KO) and CRTH2 KO hearts, while could not in FP KO hearts. (6) PGD2-dominated activation of prostanoid biosynthesis by dexamethasone alleviates myocardial ischemia-reperfusion injury in both DP KO and CRTH2 KO hearts to the same levels as observed in wild-type hearts. This cardioprotective effect is completely abrogated by pharmacological inhibition of ERK or a genetic disruption of the FP receptor.
Conclusions: PGD2 protects cardiomyocytes against ischemia-reperfusion injury via the FP receptor. ERK is the major downstream kinase responsible for PGD2-mediated cardioprotection.
- © 2010 by American Heart Association, Inc.