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

Abstract

Background and purpose: Our study aimed to explore the mechanistic network of toll-like receptor 2 (TLR2)/activator protein-1 (AP-1) combined with SOX10 activation of the mitogen-activated protein kinase (MAPK) pathway via connective tissue growth factor (CTGF) in doxorubicin (Dox)-induced myocardial injury.

Experimental approach: 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 the MAPK pathway. H9c2 cell injury was assessed by testing cell viability, lactate dehydrogenase (LDH) release and mitochondrial membrane potential.

Key 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 of 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 and implications: TLR2 activates AP-1 which cooperates with SOX10 to promote CTGF transcription and subsequently activate the MAPK pathway, thereby stimulating Dox-induced myocardial injury.