Inhibitory effect of melatonin on necroptosis via repressing the Ripk3-PGAM5-CypD-mPTP pathway attenuates cardiac microvascular ischemia-reperfusion injury

Journal of Pineal Research
Hao ZhouYingmei Zhang

Abstract

The molecular features of necroptosis in cardiac ischemia-reperfusion (IR) injury have been extensively explored. However, there have been no studies investigating the physiological regulatory mechanisms of melatonin acting on necroptosis in cardiac IR injury. This study was designed to determine the role of necroptosis in microvascular IR injury, and investigate the contribution of melatonin in repressing necroptosis and preventing IR-mediated endothelial system collapse. Our results demonstrated that Ripk3 was primarily activated by IR injury and consequently aggravated endothelial necroptosis, microvessel barrier dysfunction, capillary hyperpermeability, the inflammation response, microcirculatory vasospasms, and microvascular perfusion defects. However, administration of melatonin prevented Ripk3 activation and provided a pro-survival advantage for the endothelial system in the context of cardiac IR injury, similar to the results obtained via genetic ablation of Ripk3. Functional investigations clearly illustrated that activated Ripk3 upregulated PGAM5 expression, and the latter increased CypD phosphorylation, which obligated endothelial cells to undergo necroptosis via augmenting mPTP (mitochondrial permeability transition...Continue Reading

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Citations

Sep 8, 2018·Journal of Cellular Physiology·Junqin ShengJianxun Feng
Dec 13, 2019·Journal of Receptor and Signal Transduction Research·Yunpeng TianHaoming Song
Dec 21, 2019·Journal of Receptor and Signal Transduction Research·Yang YangZhiyun Wang
Jan 29, 2020·Journal of Receptor and Signal Transduction Research·Peng LiQiuyun Tu
Feb 20, 2020·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Xiufeng YuDaling Zhu
Jul 15, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jinghui YangLiming Wang
Jul 11, 2020·Reproduction in Domestic Animals = Zuchthygiene·Yi FangRongzhen Zhong
Sep 15, 2020·Frontiers in Cell and Developmental Biology·Chen LiJianqiu Liang
Nov 14, 2019·Cell Death & Disease·Tamás MolnárGábor Koncz
May 16, 2020·Frontiers in Physiology·Zhenhong FuYundai Chen
Mar 3, 2020·Frontiers in Pharmacology·Yun ChenGuoliang Meng

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