Protective effects of valsartan administration on doxorubicin­induced myocardial injury in rats and the role of oxidative stress and NOX2/NOX4 signaling.

ABSTRACT

Clinical application of doxorubicin (DOX) is hampered by its potential cardiotoxicity, however angiotensin receptor blockers could attenuate DOX­induced cardiomyopathy. The present study tested the hypothesis that simultaneous administration of valsartan (Val) with DOX could prevent DOX­induced myocardial injury by modulating myocardial NAD(P)H oxidase (NOX) expression in rats. Eight­week­old male Sprague­Dawley rats were randomly divided into control (CON), DOX, and DOX+Val groups. After 10 weeks, surviving rats underwent echocardiography examination, myocardial mRNA and protein expression detection of NOX1, NOX2 and NOX4. H9C2 cells were used to perform in vitro experiments, reactive oxygen species (ROS) production and apoptosis were observed under the conditions of down­ or upregulation of NOX2 and NOX4 in DOX­ and DOX+Val­treated H9C2 cells. Cardiac function was significantly improved, pathological lesion and collagen volume fraction were significantly reduced in the DOX+Val group compared with the DOX group (all P<0.05). Myocardial protein and mRNA expression of NOX2 and NOX4 was significantly downregulated in DOX+Val group compared with in the DOX group (all P<0.05). In vitro, ROS production and apoptosis in DOX­treated H9C2 cells was significantly reduced by NOX2­small interfering (si)RNA and NOX4­siRNA, and significantly increased by overexpressing NOX2 and NOX4. To conclude, Val applied simultaneously with DOX could prevent DOX­induced myocardial injury and reduce oxidative stress by downregulating the myocardial expression of NOX2 and NOX4 in rats.