Protective effect of Di'ao Xinxuekang capsule against doxorubicin-induced chronic cardiotoxicity

Di'ao Xinxuekang capsule (DXXK) extracted from Dioscorea nipponica Makino is a well-known traditional Chinese herbal medicinal product widely used in the treatment of cardiovascular disease, such as myocardial ischemia and arrhythmia. The active ingredients of DXXK were also traditionally utilized for treating cardiovascular disease in the former Soviet Union after the 1960s. As a specific type of cardiovascular disease, doxorubicin (DOX)-induced cardiotoxicity is characterized by arrhythmia, myocardial ischemia, and heart failure.This study aimed to investigate the potential protective effect of DXXK against chronic cardiotoxicity induced by DOX.A mouse model of chronic cardiotoxicity induced by DOX and an in vitro model of DOX-induced myocardial damage were created to assess the protective effect of DXXK. Cardiac functional parameters, serum levels of CK-MB and LDH and cardiac histopathological indicators were determined in the mouse model. Moreover, cell viability was measured by the MTT method, and the effect of DXXK on the anticancer activity of DOX was also investigated by utilizing 4T1, HepG2, and H460 cell lines. Furthermore, the levels of markers of oxidative stress indexes (SOD, GSH, MDA) and inflammation (TNF-α, IL-1α) were measured using biochemical and Elisa kits, respectively. The level of ROS in H9c2 cardiomyocyte was determined by flow cytometry. The protein expression levels of HIF-1α and NF-κB p65 were measured by western blotting. Finally, molecular docking was performed to visualize the patterns of interactions between the effective molecule and targeted protein.DXXK alleviated DOX-induced chronic cardiotoxicity as shown by the reversal of changes in levels of myocardial enzymes and left ventricular function and structure. DXXK exhibits antioxidant and anti-inflammatory activities. We also observed that DXXK might increase the protein expression level of HIF-1α and decrease the protein expression level of NF-κB p65. Further results of in vitro experiments showed that DXXK could protect cardiomyocyte against DOX-induced production of ROS, but DXXK had no effect on the anticancer activity of DOX. The results of molecular docking showed that dioscin and pseudoprotodioscin were the top two compounds of DXXK, which had high affinity with HIF-1α and NF-κB p65.Our results indicated that DXXK could protect against cardiotoxicity induced by DOX and alleviate oxidative stress and inflammation in vivo and in vitro via the regulation of HIF-1α and down NF-κB p65.