Repurposing mesalazine against cardiac fibrosis in vitro

Cardiovascular diseases are exacerbated and driven by cardiac fibrosis. TGF beta induces fibroblast activation and differentiation into myofibroblasts that secrete excessive extracellular matrix proteins leading to stiffening of the heart, concomitant cardiac dysfunction, and arrhythmias. However, effective pharmacotherapy for preventing or reversing cardiac fibrosis is presently unavailable. Therefore, drug repurposing could be a cost- and time-saving approach to discover antifibrotic interventions. The aim of this study was to investigate the antifibrotic potential of mesalazine in a cardiac fibroblast stress model. TGF beta was used to induce a profibrotic phenotype in a human cardiac fibroblast cell line. After induction, cells were treated with mesalazine or solvent control. Fibroblast proliferation, key fibrosis protein expression, extracellular collagen deposition, and mechanical properties were subsequently determined. In response to TGF beta treatment, fibroblasts underwent a profound phenoconversion towards myofibroblasts, determined by the expression of fibrillary alpha SMA. Mesalazine reduced differentiation nearly by half and diminished fibroblast proliferation by a third. Additionally, TGF beta led to increased cell stiffness and adhesion, which were reversed by mesalazine treatment. Collagen 1 expression and deposition-key drivers of fibrosis-were significantly increased upon TGF beta stimulation and reduced to control levels by mesalazine. SMAD2/3 and ERK1/2 phosphorylation, along with reduced nuclear NF kappa B translocation, were identified as potential modes of action. The current study provides experimental pre-clinical evidence for antifibrotic effects of mesalazine in an in vitro model of cardiac fibrosis. Furthermore, it sheds light on possible mechanisms of action and suggests further investigation in experimental and clinical settings.

Automated summary

The study demonstrated that mesalazine has antifibrotic effects in an in vitro model of cardiac fibrosis, reducing fibroblast proliferation and differentiation, regulating collagen deposition, and promoting decreased cell stiffness and adhesion. Furthermore, the drug may exert its antifibrotic action by modulating the SMAD2/3 and ERK1/2 signaling pathways, along with NF-κB nuclear translocation.