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.
Highlights
Fibrosis is the excessive deposition of extracellular matrix (ECM) proteins, leading to organ dysfunction, morbidity and death
As the availability of primary human cardiac fibroblasts is limited, we recently established the human atrial fibroblast cell line HAF-SRK01 (Künzel et al 2020) (HAF), which was employed in this study to test potential antifibrotic effects of mesalazine
Myofibroblast differentiation was determined by the expression of fibrillary α-smooth muscle actin (αSMA) which is characteristic for myofibroblasts (Baum and Duffy 2011)
Summary
Fibrosis is the excessive deposition of extracellular matrix (ECM) proteins, leading to organ dysfunction, morbidity and death. The burden of fibrosis is substantial, as 25% of the population are affected and approximately 45% of deaths in the Western world can be attributed to diseases involving fibroproliferation (Artlett 2012; Zhao et al 2020). The human heart is vulnerable to fibrotic remodeling, as lost cardiomyocytes do not regenerate and are replaced by ECM proteins (Uygur and Lee 2016). Cardiac fibroblasts safeguard the ECM homeostasis by well-balanced secretion and degradation of ECM proteins, ensuring optimal tissue mechanical properties. Thereby, they protect the heart from rupture due to high mechanical load without negatively
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