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 (AMPKα) 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 (VDAC1) oligomerization,
hexokinase 2 (HK2) liberation,
mitochondrial permeability transition pore (mPTP) opening, PINK1/Parkin upregulation, and ultimately mitophagy-mediated
CMEC death. However,
melatonin strengthened
CMEC survival via activation of AMPKα, followed by p-Drp1S616 downregulation and p-Drp1S37 upregulation, which blunted Drp1-dependent mitochondrial fission. Suppression of mitochondrial fission by
melatonin recovered VDAC1-HK2 interaction that prevented
mPTP opening and PINK1/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-VDAC1-HK2-mPTP-mitophagy axis via activation of AMPKα.