Abstract
Excessive or uncontrolled mitophagy may result in a drastic shortage of healthy mitochondrial for ATP supply after reperfusion, leading to irreversible myocardial damage. Melatonin, a hormone produced by the pineal gland, has been proven to ameliorate myocardial ischemia-reperfusion (I/R) injury via regulating mitophagy. However, its underlying mechanism has not been fully elucidated. The present study focused on the role of mitophagy in the cardioprotective effects of melatonin by using the myocardial I/R rat model. The rats were pretreated with or without the apelin inhibitor ML221, the sirtuin 3 (SIRT3) inhibitor 3-TYP and then subjected to I/R injury, with melatonin administrated 10 min before reperfusion. The effects of melatonin on myocardial infarct size, biomarkers of myocardial injury, oxidative stress, and mitochondrial function were detected, and the expression of apelin, SIRT3, and mitophagy-related proteins were also measured. Excessive mitophagy was activated after I/R injury and was correlated with oxidative stress and mitochondrial dysfunction. Melatonin pretreatment ameliorated myocardial injury by decreasing oxidative stress, restoring mitochondrial function, and inhibiting excessive mitophagy. However, ML221 or 3-TYP disrupted these beneficial effects of melatonin on I/R injury. Taken together, these results suggest that melatonin pretreatment ameliorates myocardial I/R injury through regulating the apelin/SIRT3 pathway to inhibit excessive mitophagy.
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