Wnt/β-catenin antagonist pyrvinium rescues high dose isoproterenol induced cardiotoxicity in rats: Biochemical and immunohistological evidences

The up-regulation of Wnt/β-catenin pathway induces cardiac function abnormalities, hypertrophy, and fibrosis in diabetic hypertensive and pressure overload models. The present study investigates the cardioprotective effects of Wnt/β-catenin inhibition on isoproterenol (ISO) induced cardiotoxicity in rats. ISO was administered at a dose of 85 mg/kg (s.c) for 2 days. Wnt/β-catenin inhibitor pyrvinium (60 μg/kg, p.o) was given 2h prior and glibenclamide at a dose of 5 mg/kg; p.o, 2 h after ISO injection. Cardiac function parameters were assessed on isolated hearts by using automated Biopac apparatus. The β-catenin transcription and expression was detected by RT-PCR technique and immunohistochemical method. Serum and cardiac tissue biochemical changes including cardiac troponin-I, CK-MB, LDH, anti-oxidant enzyme levels, inflammatory cytokines, and membrane associated Na+/K + ATPase and Ca2+ATPase and caspase-3 activity, collagen content, fibronectin protein levels were evaluated in various study groups. Histological studies were also carried out to analyze the cardiomyocyte damage, hypertrophy, fibrosis, and necrosis, while α-SMA, TGF-β expression was checked by immunostaining. ISO administration enhanced β-catenin gene expression and transcription which promoted oxidative and nitrosative stress, inflammatory cytokine release, reduced ATP levels, induced over-expression of fibrotic proteins resulting in cardiac hypertrophy, myocardial necrosis, functional and histological changes. However, antagonism of Wnt/β-catenin pathway attenuated these ISO induced pathological manifestations. Notably, the co-treatment with ATP-sensitive K+ channel inhibitor partially, reduced the cardioprotective effects of Wnt/β-catenin blocker pyrvinium in ISO rats. Thus Wnt/β-catenin inhibition exhibits cardioprotective in ISO model by anti-oxidant, anti-inflammatory, anti-fibrotic properties and by possible involvement of ATP-sensitive potassium channel activation.