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
PGD(2) biosynthesis. We examined a downstream mechanism of cardioprotection elicited by
PGD(2) biosynthesis. Acute
PGD(2) treatment did not protect hearts against I/R injury. We then speculated that
PGD(2) and its metabolite 15-deoxy-Δ12,14-PGJ(2) 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
PGD(2) receptors (ie, DP1 and DP2) in the heart but abundant expression of
PGF(2α) receptor (FP), which binds
PGF(2α) and
PGD(2) with equal affinity.
Glucocorticoids also failed to induce the expression of L-PGDS-dependent Nrf2 target genes in FP-knockout hearts.
PGD(2) acted through its metabolite 15-deoxy-Δ12,14-PGJ(2) 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,
PGD(2) 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
PGD(2) (15-deoxy-Δ12,14-PGJ(2)) as another mechanism by which
glucocorticoids induce cardioprotection.