State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
Tianjin Key Laboratory of Metabolic Diseases and Department of Physiology, Tianjin Medical University, Tianjin, 300070, China.
Nat Commun. 2019 Apr 23;10(1):1888. doi: 10.1038/s41467-019-09492-4.
The use of nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase (COX)-1 and COX-2, increases heart failure risk. It is unknown whether microsomal (m) prostaglandin (PG) E synthase (S)-1, a target downstream of COX, regulates myocardial (M) ischemia/reperfusion (I/R) injury, a key determinant of heart failure. Here we report that COX-1 and mPGES-1 mediate production of substantial amounts of PGE and confer cardiac protection in MI/R. Deletion of mPges-1 impairs cardiac microvascular perfusion and increases inflammatory cell infiltration in mouse MI/R. Consistently, mPges-1 deletion depresses the arteriolar dilatory response to I/R in vivo and to acetylcholine ex vivo, and enhances leukocyte-endothelial cell interaction, which is mediated via PGE receptor-4 (EP4). Furthermore, endothelium-restricted Ep4 deletion impairs microcirculation, and exacerbates MI/R injury, irrespective of EP4 agonism. Treatment with misoprostol, a clinically available PGE analogue, improves microcirculation and reduces MI/R injury. Thus, mPGES-1, a key microcirculation protector, constrains MI/R injury and this beneficial effect is partially mediated via endothelial EP4.
使用抑制环氧化酶（COX）-1 和 COX-2 的非甾体抗炎药会增加心力衰竭的风险。尚不清楚微粒体（m）前列腺素（PG）E 合酶（S）-1（COX 的下游靶点）是否调节心肌（M）缺血/再灌注（I/R）损伤，这是心力衰竭的关键决定因素。在这里，我们报告 COX-1 和 mPGES-1 介导大量 PGE 的产生，并在 MI/R 中赋予心脏保护作用。mPges-1 的缺失会损害小鼠 MI/R 中的心肌微血管灌注并增加炎症细胞浸润。一致地，mPges-1 的缺失会抑制体内 I/R 以及乙酰胆碱的体外对小动脉的扩张反应，并增强白细胞-内皮细胞相互作用，这是通过 PGE 受体-4（EP4）介导的。此外，内皮细胞特异性 Ep4 缺失会损害微循环，并加重 MI/R 损伤，而与 EP4 激动剂无关。使用米索前列醇（一种临床可用的 PGE 类似物）治疗可改善微循环并减少 MI/R 损伤。因此，作为关键的微循环保护剂，mPGES-1 限制了 MI/R 损伤，这种有益作用部分是通过内皮细胞 EP4 介导的。
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