Ivabradine prevents doxorubicin-induced cardiotoxicity via attenuating mitochondrial dysfunction and mitochondrial dynamic imbalance in H9C2 cells and rats

Abstract

Abstract Background Doxorubicin (DOX) is a widely used chemotherapeutic agent, and cardiotoxicity is one of its well-known side effects, which is mediated by cardiac mitochondrial dysfunction. Ivabradine (IVA), a heart rate reduction drug, exerts benefits in various cardiac diseases as shown in both preclinical and clinical studies. However, its roles on DOX-induced cardiotoxicity have never been investigated. Purpose We determined whether IVA reduces DOX-induced cardiotoxicity by directly promoting mitochondrial function and maintaining mitochondrial dynamic balance. Methods H9C2 cells were divided into 4 groups: 1) Control, 2) DOX (10 μM, 25 h), 3) IVA (3 μM, 25 h), 4) Pretreatment with IVA (3 μM, 1 h), followed by DOX treatment (10 μM, 24 h). Then, cell viability and mitochondrial function were determined. In animal study, male Wistar rats were divided into 4 groups: 1) Control, 2) IVA (10 mg/kg/d, PO), 3) DOX (3 mg/kg/d, 6 doses, IP), 4) Co-treatment with IVA (10 mg/kg/d, PO) and DOX (3 mg/kg/d, 6 doses, IP) for 30 days. Then, heart rate, cardiac function, and cardiac mitochondrial dynamic proteins were determined. Result DOX reduced %cell viability of H9C2 cells via increasing cellular and mitochondrial oxidative stress, and reducing mitochondrial respiration (Figure 1A, B). Under DOX-induced cellular injury condition, pretreatment with IVA resulted in increasing %cell viability by 11%, decreasing cellular and mitochondrial oxidative stress; however, IVA did not affect mitochondrial respiration. Consistent with in vitro study, DOX induced cardiac dysfunction as indicated by reduced heart rate and ejection fraction, impaired mitochondrial function and mitochondrial dynamics balance (Figure 1C, D). Co-treatment with DOX and IVA had no further impact on heart rate. DOX-IVA attenuated cardiac mitochondrial dysfunction and mitochondrial dynamics imbalance, thus prevented cardiac dysfunction. Conclusion IVA effectively protected against DOX-induced cardiotoxicity through improvement of mitochondrial function, mitochondrial dynamics, and reduction of oxidative stress. These findings suggest the therapeutic potential of IVA in preventing Dox-induced cardiotoxicity.