LSD1 demethylase inhibition prevents cardiac fibrosis in both ischemic and congenital diseases in mice and pig models

Abstract

Fibrosis is part of a clinical burden in cardiovascular diseases. The pathological process has been the subject of intensive research with still mitigated therapeutic options. Recently chromatin modifiers have turned out to be potential drugs to modulate fibrosis. Here, in order to address the question of pharmacological inhibition of fibrosis, we used both a mouse model of myocardial infarction with left ventricular fibrosis and a more clinically relevant pig model of right ventricular failure featuring interstitial fibrosis. Treatment of these diseased animal models with an inhibitor of the Lysine Demethylase 1 (LSD1) significantly prevented both left and right ventricular failure in both the mouse and the pig, respectively. This was revealed by a significant recovery of left ventricular function post-myocardial infarction in the mouse and a limitation of remodeling of the pig right ventricle, thus preserving its function. Fibrosis was significantly decreased in both mouse and pig hearts, which likely account for improvement in ventricular function. We thus provide evidence of the beneficial effect of LSD1 inhibitors in cardiac fibrosis and of the use of such drugs to preserve ventricular function in both ischemic and congenital heart diseases. NEW & NOTEWORTHYDrugs to prevent cardiac fibrosis has been the subject of intensive research with limited outcomes. This work inspired by oncology, provides evidence that an epigenetic modifier which targets the process of epithelial-to-mesenchymal transition turns out to be an efficient inhibitor of fibrosis for both ischemic and non-ischemic myocardial diseases.