Empagliflozin alleviates myocardial I/R injury and cardiomyocyte apoptosis via inhibiting ER stress-induced autophagy and the PERK/ATF4/Beclin1 pathway
Abstract
Abstract To explore the mechanisms underlying the specific inhibitor targeting SGLT-2 empagliflozin in alleviating myocardial ischaemia–reperfusion (I/R) injury. A mouse model of I/R injury and H2O2-induced H9C2 cell model were established. The expressions of Bcl-2, Bax, LC3, Beclin1, GRP78, CHOP, PERK, ATF4, ATF6, IREα and P62 were examined by western blot, immunofluorescence or immunohistochemistry staining, respectively. The cardiac function was measured by echocardiography, TCC staining, lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) activity. Cell apoptosis was analysed by TUNEL, Annexin V/propidium iodide (PI) staining and caspase 3 and 9 activities. CCK-8 assay was used for analysing cell viability. PBA, TUDC and 3-MA were utilised for blocking ER stress and autophagy, respectively. Empagliflozin suppressed myocardial I/R injury in vivo and H2O2-induced cardiomyocyte apoptosis in vitro. Blockade of ER stress and autophagy inhibited H2O2-induced cardiomyocyte apoptosis. ER stress activated autophagy through the PERK signalling in H2O2-treated H9C2 cells. Empagliflozin suppressed ER stress-induced autophagy by inhibiting the PERK/ATF4/Beclin1 signalling. H2O2 and I/R-induced cardiomyocyte apoptosis was restrained by empagliflozin through inhibition of ER stress-induced autophagy. Empagliflozin suppressed ER stress-induced autophagy via suppressing the PERK/ATF4/Beclin1 signalling, thus alleviating myocardial I/R injury and cardiomyocyte apoptosis.
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