TLR2 activates AP-1 to facilitate CTGF transcription and stimulate doxorubicin-induced myocardial injury

Abstract

Objective: Our study aimed to explore the mechanism network that TLR2/AP-1 combined with SOX10 to activate the MAPK pathway via CTGF in Dox-induced myocardial injury. Methods: Rats with Dox-induced myocardial injury were treated with a TLR2 inhibitor or CTGF silencing lentiviral vector. H9c2 cells were treated with genetic vectors or MAPK pathway activators. Cardiac function was tested using echocardiography and serum markers. H&E, sirius red, and TUNEL staining were used to detect myocardial pathological changes, collagen accumulation, and apoptosis. Western blot was used to detect proteins related to cardiac hypertrophy, fibrosis, apoptosis, and MAPK pathway. H9c2 cell injury was assessed by testing cell viability, LDH release, and mitochondrial membrane potential. Results: TLR2 and CTGF were highly expressed in patients with heart failure, and Dox treatment further increased their expression. Inhibiting TLR2 or silencing CTGF improved cardiac function and reduced myocardial fibrosis and apoptosis in Dox-treated rats. Silencing TLR2 alleviated Dox-induced H9c2 cell injury, which was nullified by CTGF overexpression. TLR2 activated AP-1, which cooperated with SOX10 to promote CTGF transcription. MAPK activation aggravated H9c2 cells against Dox-induced injury. Conclusions: TLR2 activates AP-1 which cooperates with SOX10 to promote CTGF transcription and subsequently activate the MAPK pathway, thereby stimulating Dox-induced myocardial injury.