Galectin-3 inhibition attenuates doxorubicin-induced cardiac dysfunction by upregulating the expression of peroxiredoxin-4.

Doxorubicin (DOX) is a highly efficient chemotherapeutic drug limited by its cardiotoxicity. Galectin-3 (Gal-3) overexpression is associated with several cardiovascular diseases. In this study, the in vivo models of DOX-treated rats and the in vitro model of DOX-treated H9C2 cells were used. DOX induced cardiac injury and dysfunction accompanied with the upregulation of Gal-3 at the end of the experiment, while inhibition of Gal-3 with modified citrus pectin (MCP) exhibited a dramatic improvement in cardiac function of the DOX-treated rats, as manifested by increased left ventricular systolic pressure and ±d/d and decreased left ventricular end-diastolic pressure. The plasma levels of myocardial injury markers such as lactate dehydrogenase, creatine kinase, creatine kinase-MB, and cardiac troponin I were decreased after MCP treatment. In parallel, MCP attenuated myocardial tissue markers of oxidative stress such as hydrogen peroxide and malondialdehyde restored the activities of superoxide dismutase, catalase, and glutathione peroxidase and upregulated antioxidant peroxiredoxin-4 (Prx-4). To further verify the role of Prx-4, it was downregulated by siRNA-mediated knockdown in H9C2 cells. MCP could not reverse DOX-induced oxidative stress in Prx-4-knock-down cells. In conclusion, Gal-3 mediated DOX-induced cardiotoxicity and Gal-3 inhibition attenuated DOX-induced cardiac dysfunction by upregulating the expression of Prx-4 to reduce myocardial oxidative stress.