Resveratrol Pretreatment Alleviates Myocardial Ischemia/reperfusion Injury Via Inhibiting STIM1 Mediated Intracellular Calcium Accumulation

Objective:Previous studies have demonstrated STIM1-mediated store-operated Ca²⁺entry?SOCE?contributes to intracellular Ca²⁺accumulation in H9C2 cells subjected to hypoxia/reoxygenation?H/R?injury.The present study aimed to investigate the effect of resveratrol on STIM1 mediated intracellular Ca²⁺accumulation and subsequent cell death in the context of myocardial ischemia/reperfusion?I/R?injury.Methods:C57 BL/6 mice were fed either saline or resveratrol?50 mg/kg daily for 2weeks?and then subjected to myocardial I/R injury.TTC/Evans Blue staining and TUNEL assay were performed to quantify the infarct size and apoptosis index.The cardiac function was evaluated by echocardiography.Neonatal rat ventricular cardiomyocytes?NRVCs?underwent hypoxia/reoxygenation?H/R?to establish the in vitro model.To achieve over-expression,NRVCs was transfected with STIM1-adenovirus vector.Apoptosis was analyzed by both flow cytometry and TUNEL assay.Cell viability was measured by MTS assay and cell necrosis was determined by LDH release assay.Intracellular Ca²⁺concentration was detected by laser scanning confocal microscopy using Fluo-3/AM probe.Results:Resveratrol significantly reduced apoptosis,decreased infarct size and improved cardiac function in mice subjected to myocardial I/R injury.In NRVCs,resveratrol also down-regulated STIM1 expression accompanied by decreased intracellular Ca²⁺accumulation elicited by H/R injury.In addition,resveratrol reduced cell apoptosis,upregulated the Bcl-2,decreased Bax and cleaved caspase-3expression.Furthermore,the effects of resveratrol on STIM1 mediated intracellular Ca²⁺accumulation,apoptotic proteins,and H/R induced cell injury were exacerbated by STIM1 overexpression and partly abolished by SOCE inhibitor SKF96365 in NRVCs in vitro.Conclusion:Our findings demonstrate that resveratrol exerts anti-apoptotic and improves cardiac functional recovery following myocardial I/R by inhibiting STIM1-induced intracellular Ca²⁺ accumulation.