Empagliflozin attenuates doxorubicin-induced cardiotoxicity by activating AMPK/SIRT-1/PGC-1α-mediated mitochondrial biogenesis

Abstract

We aimed to probe the functions and possible mechanisms of empaglif lozin in doxorubicin (Dox)-caused cardiotoxicity. First, a cardiotoxicity rat model was built by continuously injecting Dox intraperitoneally. Then, empaglif lozin (30 mg/kg) was gavaged into the rats. Next, echocardiography was utilized for checking the cardiac function of rats, and H&E staining for observing pathological alterations of the myocardial tissues. Besides, biochemical assays and Enzyme-linked Immunosorbent Assay were adopted to detect the creatine kinase isoenzyme (CK-MB), N-terminal pro-brain natriuretic peptide (NT-proBNP), adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) levels in rat serum and superoxide dismutase (SOD), malondialdehyde acid (MDA), and catalase (CAT) in myocardial tissue, respectively. Furthermore, the expression of AMPK/SIRT-1/PGC-1α signaling pathway-related proteins in the myocardial tissues was tested by Western blot. Continuous intraperitoneal injection of Dox greatly elevated left ventricular end-systolic diameter (LVESD) and left ventricular end-diastolic diameter (LVEDD), reduced fractional shortening (FS) and ejection fraction (EF), and notably up-regulated CK-MB and NT-proBNP level in rats’ serum, thus impairing cardiac function. Empaglif lozin treatment could ameliorate myocardial histopathological damage and alleviate cardiac function and tissue damage by down-regulating LVEDD and LVESD, up-regulating EF and FS, and inhibiting CK-MB and NT-proBNP level in serum. Additionally, empaglif lozin improved Dox-induced excessive oxidative stress and dysregulation of energy metabolism. Furthermore, empaglif lozin activated the AMPK/SIRT-1/PGC-1α signaling pathway in Dox-caused cardiotoxicity rats. In conclusion, in addition to bettering the cardiac tissue and function injury caused by Dox, empaglif lozin also improves excessive oxidative stress and energy metabolism. Notably, empaglif lozin may exert cardioprotective effects through activating the AMPK/SIRT-1/PGC-1α pathway.