Polypyrimidine tract binding protein 1 exacerbates cardiac fibrosis by regulating fatty acid-binding protein 5

The activation of cardiac fibroblasts (CFs) leads to overproduction of collagens and subsequently cardiac fibrosis. However, the regulatory mechanism of CF function in the process of cardiac fibrosis remains unclear. This work investigated the function of polypyrimidine tract binding protein 1 (PTBP1)/nuclear receptor NR4A1 (Nur77)/fatty acid-binding protein 5 (FABP5) axis in myocardial fibrosis.

Cardiac fibrosis was induced in mice suffered left anterior descending ligation. In parallel, neonatal mouse CFs were isolated and stimulated with transforming growth factor-β1 (TGF-β1). Cardiac fibrosis was evaluated by Masson's trichrome staining. Expression of PTBP1, Nur77, FABP5, collagen I, and collagen III was measured by quantitative real-time PCR and western blotting. Proliferation of CFs was assessed by 5-ethynyl-2'-deoxyuridine assay. Molecular interaction was validated by RNA-binding protein immunoprecipitation, chromatin immunoprecipitation, and dual luciferase reporter assay. PTBP1 was up-regulated (P < 0.05), whereas Nur77 (P < 0.05) and FABP5 (P < 0.05) were down-regulated in the fibrotic hearts of mice and TGF-β1-exposed CFs. PTBP1 overexpression facilitated proliferation (P < 0.05) and collagen I (P < 0.05) and collagen III (P < 0.05) expression of CFs after stimulation with TGF-β1. PTBP1 reduced Nur77 stability (P < 0.05) to inhibit Nur77 expression (P < 0.05) in CFs. Nur77 bound to FABP5 promoter to promote the transcription (P < 0.05) and expression (P < 0.05) of FABP5. Silencing of Nur77 or FABP5 abolished the inhibitory effect of PTBP1 knockdown on proliferation (P < 0.05) and collagen I (P < 0.05) and collagen III (P < 0.05) expression of CFs in vitro. PTBP1 depletion ameliorated cardiac fibrosis (P < 0.05), α-smooth muscle actin (P < 0.05), and collagen I (P < 0.05) expression in myocardial infarction mice through regulating Nur77/FABP5 pathway (P < 0.05) in vivo.

PTBP1 contributed to cardiac fibrosis via promoting CF proliferation and collagen deposition through Nur77 mRNA decay and subsequent transcription inhibition of FABP5. Our findings suggest that PTBP1/Nur77/FABP5 axis may be potential targets for cardiac fibrosis therapy.