Ranolazine exerts cardioprotection through attenuating mitochondrial dynamic imbalance in trastuzumab-induced cardiotoxicity in rats

Trastuzumab, a potent chemotherapeutic agent, has been associated with serious cardiotoxic side effects, which frequently result in its discontinuation in clinical practice. Ranolazine, a medication widely used to treat chronic angina patients, has recently been documented to diminish cardiotoxicity following chemotherapies. However, the molecular mechanisms behind the cardioprotective effects of ranolazine on mitochondrial function and dynamics in the trastuzumab-treated rats have never been elucidated. We hypothesized that ranolazine exerts cardioprotection against trastuzumab-mediated cardiotoxicity via mitochondrial protection. Male Wistar rats were randomly assigned to either a control group receiving normal saline (Con, n = 8) or a trastuzumab-treated group (Trz, 4 mg/kg/day for 7 days, n = 16). The rats in the trastuzumab group were further divided to receive either oral normal saline (Trz, n = 8) or ranolazine (Ran, 305 mg/kg/day, n = 8) concurrently for 7 days. After the treatment period, assessments of cardiac function and biochemical markers were conducted. Trastuzumab caused mitochondrial dysfunction, impaired mitochondrial dynamics, excessive oxidative damage, inflammation, and autophagic dysregulation, resulting in cardiomyocyte death and cardiac dysfunction. Co-treatment with ranolazine effectively attenuated those cardiac adverse effects induced by trastuzumab, leading to improved heart function. Ranolazine provides cardioprotective effects against trastuzumab-induced cardiotoxicity by mitigating mitochondrial dysfunction, mitochondrial dynamic imbalance, oxidative stress, inflammation, and cardiomyocyte apoptosis in the heart. Ranolazine administration warrants further investigation as a potential adjunctive treatment to mitigate cardiotoxic effects associated with trastuzumab therapy.