Ameliorative effect of inhibitors of tyrosine kinase and TGF-β in the doxorubicin-induced myocardial fibrosis in rats

Abstract

Myocardial fibrosis is a major global health issue that is linked to practically all types of heart disease. Inhibiting the TGF-β signalling pathway is currently of great interest due to its well-established role in cardiac fibrosis. To order avoid heart failure, it's essential to prevent cardiac fibrosis. However, there is currently no effective therapeutic approach. The objective of the present study was to evaluate the effect of Nintedanib (tyrosine kinase inhibitor) and Pirfenidone (TGF- β inhibitor) in the treatment of cardiac fibrosis. Cardiac fibrosis was induced by Doxorubicin (2.5 mg/kg/day, i.p. 3 times a week). Cardiac fibrosis is confirmed by ST-segment elevation. Confirmed cardiac fibrotic rats were treated with Nintedanib (30 and 50 mg/kg, p.o.) and Pirfenidone (50 and 100 mg/kg, p.o.) for 2 weeks. The treatment of Nintedanib and Pirfenidone remarkably minimized ST-segment elevation, decreased heart rate, heart weight, LVWI, RVWI and increased blood pressure. Combination treatment of Nintedanib and Pirfenidone normalized oxidative stress with a significant (p<0.0001) rise in the level of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) and reduced lipid peroxidation (LPO) as compared to the doxorubicin group. Further, histopathological studies confirmed the protective effects of Nintedanib and Pirfenidone on heart tissues. The present study revealed that Nintedanib and Pirfenidone, as monotherapy as well as in combination, have an anti-fibrotic effect against cardiac fibrosis. The anti-fibrotic effect could be attributed to a reduction in oxidative stress and collagen deposition, as well as inhibition of tyrosine kinase and TGF-β overexpression. The results provide the substantial evidences that Nintedanib and Pirfenidone offer protection against cardiac fibrosis.