Dapagliflozin alleviates high-fat-induced obesity cardiomyopathy by inhibiting ferroptosis

Abstract Dapagliflozin (Dapa), a selective sodium-glucose cotransporter 2 inhibitor, not only has a stable hypoglycemic function but also exerts a protective effect in cardiovascular diseases. The present study aimed to investigate whether Dapa could effectively protect high-fat diet (HFD)-induced obesity-related cardiomyocytes and its mechanism. Rats were fed with a HFD for 16 weeks and the obesity cardiomyopathy was confirmed by testing of metabolic parameters. The results demonstrated that Dapa treatment led to more obvious weight loss and a lower Lee’s index. Furthermore, Dapa administration reduced the lipid levels, including total cholesterol and low-density lipoprotein cholesterol levels, and improved the insulin sensitivity/resistance index, whereas the blood pressure was not markedly different after Dapa intervention. Echocardiography and histological analysis revealed that Dapa could effectively alleviate obesity-induced the myofibrils dissolved, collagen deposition and mitochondrial damage, and finally improved the heart function and cardiac remodeling. The present study also emphasized the vital role of Dapa in the protection obesity-related cardiac dysfunction and cardiac remodeling by inhibiting ferroptosis. Dapa treatment ameliorated the ferroptosis-related changes by attenuating iron ion deposition and decreased over-activation of the key factors of ferroptosis, including glutathione peroxidase 4, solute carrier family 7 member 11, transferrin 1 and ferritin heavy chain 1, in cardiomyocytes. In conclusion, Dapa exerted a direct protective effect against obesity cardiomyopathy by inhibiting ferroptosis.