Irbesartan suppresses cardiac toxicity induced by doxorubicin via regulating the p38-MAPK/NF-κB and TGF-β1 pathways.

Abstract

Doxorubicin (DOX) so far continues to be one of the most potent and effective anticancer drugs. Therefore, it is still needed to search for a safe and effective therapy that can opposite DOX-induced cardiotoxicity. Irbesartan (IRB), an angiotensin II receptor blocker, has a wide-ranging variety of biological activities. The present study was designed to explore the possible protective effects of IRB against DOX-induced cardiotoxicity and the underlying mechanisms. Rats were divided into four groups: control, IRB (40mg/kg, orally/daily) for 3weeks, DOX (2.5mg/kg, intraperitoneally/ three times weekly) for 2weeks to obtain cumulative dose of 15mg/kg, and finally IRB + DOX group. IRB inhibited cardiotoxicity induced by DOX which was evident by ECG changes, alterations of cardiac enzymes and histopathological changes. IRB improved DOX-induced alterations in oxidative/nitrosative status by decreasing lipid peroxidation and nitric oxide (NO) content in addition to increasing the antioxidant capacity. In addition, DOX triggers the cardiac expression of tumor necrosis factor-α (TNF-α) and nuclear factor kappa B (NF-κB) where IRB diminished DOX-induced alterations in theses parameters. Moreover, DOX significantly increase the expression levels of caspase-3 and transforming growth factor-beta 1 (TGF-β1), while IRB exhibited anti-apoptotic and anti-fibrotic effects where it abolished these elevations. Meanwhile, DOX-induced activation of p38-mitogen activated protein kinase (p38-MAPK) which was inhibited by IRB. Collectively, these results proposed that IRB afforded a significant protection against DOX-induced cardiac damage by means of antioxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic remodeling mechanisms. These mechanisms are possibly mediated, at least in part, by alterations of TGF-β1/p38-MAPK/NF-κB signaling.