Induction of autophagy has protective roles in imatinib-induced cardiotoxicity.

Abstract

Cardiotoxicity is one of the severe adverse effects of chemotherapeutic agents. Imatinib was previously reported to induce cardiotoxicity. Autophagy is an intracellular bulk protein and organelle degradation process, but its roles in cardiac diseases are unclear. We examined whether imatinib induces cardiomyocyte autophagy, and the role of autophagy in imatinib-induced cardiotoxicity using in vitro and in vivo experiments. In in vitro experiments, neonatal rat cardiomyocytes were treated with imatinib (1, 5, or 10 μM; 6 h). Myocyte autophagy was assessed by microtubule-associated protein light chain (LC) 3-II, beclin 1, mature cathepsin D, and acridine orange-stained mature autolysosome expression. Imatinib increased their expression, suggesting that it induced autophagy. Consequently, imatinib altered the production of mitochondria-derived reactive oxygen species (ROS) and loss of mitochondrial membrane potential, which were assessed by the fluorescent indicator MitoSOX and JC-1, respectively, leading to cardiomyocyte apoptosis. 3-methyl-adenine (3MA), an autophagic inhibitor, exacerbated imatinib-induced apoptosis by 30 %. In in vivo experiments, C57BL/6 mice were treated with imatinib (50 and 200 mg/kg/day) for 5 weeks in the presence or absence of 3MA. Echocardiographic measurement revealed that imatinib (200 mg) caused dilatation of the left ventricle (LV) and reduced LV fractional shortening. Apoptosis and LC3-II expression in cardiac tissue were increased by imatinib. Co-treatment with 3MA and imatinib further impaired imatinib-induced cardiac apoptosis and LV dysfunction. This study suggests that imatinib induces cardiomyocyte apoptosis, leading to cardiac dysfunction. Imatinib increases cardiomyocyte autophagy as a consequence of apoptosis and autophagy has a pro-survival role in imatinib-induced cardiac impairment.