Reduced silent information regulator 1 signaling exacerbates myocardial ischemia–reperfusion injury in type 2 diabetic rats and the protective effect of melatonin

Diabetes mellitus ( DM ) increases myocardial oxidative stress and endoplasmic reticulum ( ER ) stress. Melatonin confers cardioprotective effect by suppressing oxidative damage. However, the effect and mechanism of melatonin on myocardial ischemia–reperfusion ( MI /R) injury in type 2 diabetic state are still unknown. In this study, we developed high‐fat diet‐fed streptozotocin ( HFD ‐ STZ ) rat, a well‐known type 2 diabetic model, to evaluate the effect of melatonin on MI /R injury with a focus on silent information regulator 1 ( SIRT 1) signaling, oxidative stress, and PERK / eIF 2 α / ATF 4‐mediated ER stress. HFD ‐ STZ treated rats were exposed to melatonin treatment in the presence or the absence of sirtinol (a SIRT 1 inhibitor) and subjected to MI /R surgery. Compared with nondiabetic animals, type 2 diabetic rats exhibited significantly decreased myocardial SIRT 1 signaling, increased apoptosis, enhanced oxidative stress, and ER stress. Additionally, further reduced SIRT 1 signaling, aggravated oxidative damage, and ER stress were found in diabetic animals subjected to MI /R surgery. Melatonin markedly reduced MI /R injury by improving cardiac functional recovery and decreasing myocardial apoptosis in type 2 diabetic animals. Melatonin treatment up‐regulated SIRT 1 expression, reduced oxidative damage, and suppressed PERK / eIF 2 α / ATF 4 signaling. However, these effects were all attenuated by SIRT 1 inhibition. Melatonin also protected high glucose/high fat cultured H9C2 cardiomyocytes against simulated ischemia–reperfusion injury‐induced ER stress by activating SIRT 1 signaling while SIRT 1 si RNA blunted this action. Taken together, our study demonstrates that reduced cardiac SIRT 1 signaling in type 2 diabetic state aggravates MI /R injury. Melatonin ameliorates reperfusion‐induced oxidative stress and ER stress via activation of SIRT 1 signaling, thus reducing MI /R damage and improving cardiac function.