Endogenous Prostaglandin D2 and Its Metabolites Protect the Heart Against Ischemia-Reperfusion Injury by Activating Nrf2
Endogenous Prostaglandin D2 and Its Metabolites Protect the Heart Against Ischemia-Reperfusion Injury by Activating Nrf2
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DOI：
10.1161/hypertensionaha.113.01639
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发表时间：
2014-01-01
期刊：
影响因子：
8.3
通讯作者：
Sano, Motoaki
中科院分区：
文献类型：
--
作者：
Katsumata, Yoshinori;Shinmura, Ken;Sano, Motoaki
我们最近证明，糖皮质激素通过激活脂钙素型前列腺素D（PGD）合成酶（L-PGDS）衍生的PGD(2)生物合成，显著上调心肌细胞中环氧化酶-2的表达，保护心脏免受缺血再灌注（I/R）损伤。我们研究了PGD(2)生物合成引发的心脏保护的下游机制。急性PGD(2)治疗不能保护心脏免受I/R损伤。我们推测PGD(2)及其代谢物15-脱氧-12,14- pgj(2)激活基因表达网络，介导糖皮质激素介导的心脏保护。使用无偏倚的方法，我们发现糖皮质激素以l- pgds依赖的方式诱导心脏中许多众所周知的红细胞衍生2-样2 （Nrf2）靶基因，并且在Nrf2敲除的心脏中未见糖皮质激素对I/R损伤的心脏保护作用。我们发现心脏中PGD(2)受体（即DP1和DP2）的表达相对较低，但PGF(2)受体（FP）的表达丰富，其结合PGF(2)和PGD(2)具有相同的亲和力。糖皮质激素也不能诱导fp敲除心脏中l - pgds依赖性Nrf2靶基因的表达。PGD(2)通过其代谢物15-脱氧-12,14- pgj(2)在心脏中起作用，糖皮质激素介导的过氧化物酶体增殖物激活受体-的激活证明了这一点。反过来，糖皮质激素未能诱导过氧化物酶体增殖物激活受体拮抗剂GW9662预处理的心脏中l - pgds依赖性Nrf2靶基因的表达，并且糖皮质激素介导的对I/R损伤的心脏保护作用在fp敲除小鼠和GW9662处理的小鼠中被削弱。综上所述，PGD(2)主要通过FP受体激活Nrf2来保护心脏免受I/R损伤。此外，我们提出通过PGD(2) （15-deoxy-12,14- pgj(2)）的脱水代谢物激活过氧化物酶体增殖物激活受体（15-deoxy-12,14- pgj(2)）是糖皮质激素诱导心脏保护的另一种机制。
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-12,14-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(2) receptor (FP), which binds PGF(2) 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-12,14-PGJ(2) in the heart as evidenced by the glucocorticoid-mediated activation of peroxisome proliferator-activated receptor-. In turn, glucocorticoids failed to induce the expression of L-PGDS-dependent Nrf2 target genes in hearts pretreated with peroxisome proliferator-activated receptor- 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- by the dehydrated metabolite of PGD(2) (15-deoxy-12,14-PGJ(2)) as another mechanism by which glucocorticoids induce cardioprotection.