Background: Doxorubicin (DOX) treatment is a primary cause of chemotherapy-induced cardiotoxicity. Antidiabetic sitagliptin (STG) has been shown to improve cardiovascular functions through anti-inflammatory, antioxidant, and anti-apoptotic effects. Oxidative stress plays a crucial role in the development of various cardiovascular diseases, especially those related to endothelial dysfunction. The transcription factor nuclear factor erythroid-2-like 2 (Nrf2) is the main regulator of antioxidant defense mechanisms. Nrf2, along with its suppressor protein Kelch-like ECH-associated protein 1 (Keap1), controls the levels of reactive oxygen species (ROS). Objective: This study aimed to evaluate the role of the Nrf2/caspase-3 signaling pathway in the cardiotoxic effect of DOX and the potential role of sitagliptin (STG). Materials and Methods: Rats were divided into four groups, each comprising eight animals (n=8): a control group, an STG group (receiving 10 mg/kg/day for 21 days), a DOX group (receiving 1mg/kg i.p per day for five injections week for 3 weeks) and STG+DOX group (treated by STG and DOX as previously mentioned). Results: The effect of DOX on cardiac tissue detected a significant reduction in ABP and deviated ST segment, while STG improved DOX-induced cardiotoxicity markers, oxidative stress, and inflammatory markers. Also, STG regulates cardiovascular hemodynamics and reduces both cardiac caspase-3 and Keap-1, and upregulates NrF2 gene expression levels. Conclusion: STG administration can exert protective effects against doxorubicin-induced cardiac toxicity through anti-inflammatory, antioxidant, and anti-apoptotic properties, in addition to promoting the Nrf2 signaling pathway. |
