Apelin-13 attenuates doxorubicin-induced myocardial injury via the PI3K/AKT and ERK/MAPK signaling pathways

Background: Anthracyclines play a crucial role in the chemotherapy of various malignant tumors; however, they may cause myocardial injury, which limits their clinical application. Therefore, it is of great importance to investigate drugs for the prevention and treatment of anthracycline-induced myocardial injury. The aim of this study is to evaluate the cardioprotective effects of Apelin-13 in a murine model of doxorubicin (DOX)-induced myocardial injury and to elucidate its potential underlying mechanisms. Methods: Male C57BL/6 mice (8 weeks old) were randomly assigned to four groups, with all mice received intraperitoneal injections: Control (normal saline), DOX (with a cumulative dose of 20 mg), Apelin-13 (Apelin-13 0.1 μmol/kg/d), and Apelin-13 + DOX (Apelin-13 0.1 μmol/kg/d; with a cumulative dose of 20 mg). Cardiac function was assessed using echocardiography. Histopathological changes were assessed via hematoxylin and eosin (HE) staining, and myocardial fibrosis was evaluated with Masson’s trichrome staining. Immunohistochemical analysis and terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling staining were conducted to assess protein expression and cardiomyocyte apoptosis, respectively. Protein expression levels were further validated by western blotting (WB). In vitro, rat H9C2 cardiomyocytes were cultured and divided into four groups. Control, Apelin-13 (Apelin-13 1 μM), DOX (DOX 2 μM), and Apelin-13 + DOX group (first treated with Apelin-13 1 μM, followed by DOX 2 μM after 1–2 hours). Cell viability was measured using the Cell Counting Kit-8 (CCK-8) assay. Flow cytometry was employed to quantify apoptosis, and WB was used to analyze signaling pathway components. Results: In mice studies, no mice died during or after the drug intervention period. It was found that Apelin-13 could significantly increase left ventricular ejection fraction (LVEF) and fractional shortening (FS) (P