Repurposing mesalazine against cardiac fibrosis in vitro.

Abstract

Cardiovascular diseases are exacerbated and driven by cardiac fibrosis. TGFβ 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. TGFβ 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 TGFβ treatment, fibroblasts underwent a profound phenoconversion towards myofibroblasts, determined by the expression of fibrillary αSMA. Mesalazine reduced differentiation nearly by half and diminished fibroblast proliferation by a third. Additionally, TGFβ 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 TGFβ stimulation and reduced to control levels by mesalazine. SMAD2/3 and ERK1/2 phosphorylation, along with reduced nuclear NFκB 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.

• Authors: Maximilian Hoffmann, Theresa A Kant, Ramona Emig, Johanna S E Rausch, Manja Newe, Mario Schubert, Karolina Künzel, Luise Winter, Erik Klapproth, Rémi Peyronnet, Ursula Ravens, Ali El-Armouche, Stephan R Künzel
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 394 Issue 3 Pg. 533-543 (03 2021) ISSN: 1432-1912 [Electronic] Germany
• PMID: 33064167 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Cardiotonic Agents
• Collagen Type I
• NF-kappa B
• SMAD2 protein, human
• SMAD3 protein, human
• Smad2 Protein
• Smad3 Protein
• Transforming Growth Factor beta
• Mesalamine
• Extracellular Signal-Regulated MAP Kinases

Topics

• Actins (metabolism)
• Cardiotonic Agents (pharmacology, therapeutic use)
• Cell Differentiation (drug effects)
• Cell Line
• Collagen Type I (metabolism)
• Drug Repositioning
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Fibrosis
• Humans
• Mesalamine (pharmacology, therapeutic use)
• Myocardium (metabolism, pathology)
• Myofibroblasts (drug effects, metabolism)
• NF-kappa B (metabolism)
• Smad2 Protein (antagonists & inhibitors, metabolism)
• Smad3 Protein (antagonists & inhibitors, metabolism)
• Transforming Growth Factor beta