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Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission‐ VDAC 1‐ HK 2‐ mPTP ‐mitophagy axis
Author(s) -
Zhou Hao,
Zhang Ying,
Hu Shunying,
Shi Chen,
Zhu Pingjun,
Ma Qiang,
Jin Qinhua,
Cao Feng,
Tian Feng,
Chen Yundai
Publication year - 2017
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12413
Subject(s) - mitochondrial fission , melatonin , mitophagy , vdac1 , dnm1l , reperfusion injury , voltage dependent anion channel , ampk , mitochondrion , endocrinology , ischemia , downregulation and upregulation , biology , microbiology and biotechnology , medicine , chemistry , protein kinase a , apoptosis , kinase , biochemistry , autophagy , escherichia coli , bacterial outer membrane , gene
Abstract The cardiac microvascular system, which is primarily composed of monolayer endothelial cells, is the site of blood supply and nutrient exchange to cardiomyocytes. However, microvascular ischemia/reperfusion injury ( IRI ) following percutaneous coronary intervention is a woefully neglected topic, and few strategies are available to reverse such pathologies. Here, we studied the effects of melatonin on microcirculation IRI and elucidated the underlying mechanism. Melatonin markedly reduced infarcted area, improved cardiac function, restored blood flow, and lower microcirculation perfusion defects. Histological analysis showed that cardiac microcirculation endothelial cells ( CMEC ) in melatonin‐treated mice had an unbroken endothelial barrier, increased endothelial nitric oxide synthase expression, unobstructed lumen, reduced inflammatory cell infiltration, and less endothelial damage. In contrast, AMP‐activated protein kinase α ( AMPK α) deficiency abolished the beneficial effects of melatonin on microvasculature. In vitro, IRI activated dynamin‐related protein 1 (Drp1)‐dependent mitochondrial fission, which subsequently induced voltage‐dependent anion channel 1 ( VDAC 1) oligomerization, hexokinase 2 ( HK 2) liberation, mitochondrial permeability transition pore ( mPTP ) opening, PINK 1/Parkin upregulation, and ultimately mitophagy‐mediated CMEC death. However, melatonin strengthened CMEC survival via activation of AMPK α, followed by p‐Drp1 S616 downregulation and p‐Drp1 S37 upregulation, which blunted Drp1‐dependent mitochondrial fission. Suppression of mitochondrial fission by melatonin recovered VDAC 1‐ HK 2 interaction that prevented mPTP opening and PINK 1/Parkin activation, eventually blocking mitophagy‐mediated cellular death. In summary, this study confirmed that melatonin protects cardiac microvasculature against IRI . The underlying mechanism may be attributed to the inhibitory effects of melatonin on mitochondrial fission‐ VDAC 1‐ HK 2‐ mPTP ‐mitophagy axis via activation of AMPKα.