Infliximab substantially re-silenced Wnt/β-catenin signaling and ameliorated doxorubicin-induced cardiomyopathy in rats

The release of inflammatory cytokines, namely tumor necrosis factor-alpha (TNF-alpha), plays an important role in the pathogenesis of cardiomyopathy. TNF-alpha increases in plasma and in myocardium of heart failure patients. We aimed to investigate the role of TNF-alpha inhibitor (infliximab; IFX) in regulating dilated cardiomyopathy (DCM) induced in rats. DCM was induced in rats by doxorubicin (DOX; 3.5 mg. kg(-)(1), i.p) twice weekly for 3 weeks (21 mg. kg(-1) cumulative dose). DCM rats were treated with RPL (1 mg. kg(-1) orally, daily), IFX (5 mg. kg(-1); i.p. once) or their combination for 4 weeks starting next day of last DOX dose. Echocardiography was conducted followed by a collection of blood and left ventricle (LV) for biochemical and histological investigations. DCM rats revealed deteriorated cardiac function (increased CK-MB activity, LVIDs, LVIDd, ESV, and EDV, while decreased EF% and FS%), hypertrophy (increased HW/TL, beta-MHC, and alpha-actin), inflammation (increased IL-1 beta, IL-6, and TNF-alpha). The activation of Wnt/beta-catenin along with increased gene expression of RAS components (RENIN, ACE, and AT1) were evident. LV architecture also revealed abnormalities and some degree of fibrosis. Treatment with RPL and/or IFX suppressed TNF-alpha and consequently improved most of these parameters suppressing Wnt/beta-catenin/RAS axis. Combined RPL and IFX treatment was the best among all treatments. In conclusion, Wnt/beta-catenin/RAS axis is implicated in DOX-induced cardiomyopathy. The upstream TNF-alpha was proved for the first time in-vivo to stimulate this axis where its inhibition by RPL or IFX prevented DCM. Targeting this axis at two points using RPL and IFX showed better therapeutic efficacy.

Automated summary

The release of TNF-alpha is increased in plasma and myocardium of heart failure patients, and plays an important role in the pathogenesis of cardiomyopathy. In this study, the role of TNF-alpha inhibitor (infliximab; IFX) in regulating dilated cardiomyopathy (DCM) induced in rats was investigated. Treatment with RPL and/or IFX suppressed TNF-alpha and consequently improved cardiac function, hypertrophy, and inflammation in DCM rats. Combined RPL and IFX treatment showed the best therapeutic efficacy.