Endogenous Prostaglandin D2 and Its Metabolites Protect the Heart Against Ischemia–Reperfusion Injury by Activating Nrf2
We recently demonstrated that glucocorticoids markedly upregulate the expression of cyclooxygenase-2 in cardiomyocytes and protect hearts from ischemia–reperfusion (I/R) injury by activating lipocalin-type prostaglandin D (PGD) synthase (L-PGDS)–derived PGD2 biosynthesis. We examined a downstream mechanism of cardioprotection elicited by PGD2 biosynthesis. Acute PGD2 treatment did not protect hearts against I/R injury. We then speculated that PGD2 and its metabolite 15-deoxy-Δ12,14-PGJ2 activate gene expression networks to mediate the glucocorticoid-mediated cardioprotection. Using an unbiased approach, we identified that glucocorticoids induce a number of well-known erythroid-derived 2–like 2 (Nrf2) target genes in the heart in an L-PGDS–dependent manner and that the cardioprotective effect of glucocorticoids against I/R injury was not seen in Nrf2-knockout hearts. We showed relatively low expression of PGD2 receptors (ie, DP1 and DP2) in the heart but abundant expression of PGF2α receptor (FP), which binds PGF2α and PGD2 with equal affinity. Glucocorticoids also failed to induce the expression of L-PGDS–dependent Nrf2 target genes in FP-knockout hearts. PGD2 acted through its metabolite 15-deoxy-Δ12,14-PGJ2 in the heart as evidenced by the glucocorticoid-mediated activation of peroxisome proliferator-activated receptor-γ. In turn, glucocorticoids failed to induce the expression of L-PGDS–dependent Nrf2 target genes in hearts pretreated with peroxisome proliferator-activated receptor-γ antagonist GW9662, and glucocorticoid-mediated cardioprotection against I/R injury was compromised in FP-knockout mice and GW9662-treated mice. In conclusion, PGD2 protects heart against I/R injury by activating Nrf2 predominantly via FP receptor. In addition, we propose activation of peroxisome proliferator-activated receptor-γ by the dehydrated metabolite of PGD2 (15-deoxy-Δ12,14-PGJ2) as another mechanism by which glucocorticoids induce cardioprotection.
- Received May 12, 2013.
- Revision received May 30, 2013.
- Accepted September 11, 2013.
- © 2013 American Heart Association, Inc.