LMK235 ameliorates ventricular remodelling after myocardial infarction by targeting cardiac fibroblasts and macrophages

Abstract

Abstract Objectives Histone deacetylase 4 (HDAC4)and histone deacetylase 5 (HDAC5) are two isoforms of class IIa HDACs, LMK235 is an HDAC inhibitor with higher selectivity forHDAC4/5. Here, we aimed to explorethe effects of LMK235 on ventricular remodelling after myocardial infarction (MI). Methods The MI model was established by left anterior descending branch ligation. The effects of LMK235 on cardiac dysfunction was determined by echocardiography and left ventricular pressure measurement. Fibrosis was evaluated by Masson staining and fibrotic biomarker expression, inflammation was evaluated by HE staining and inflammatory cytokine expression. In vitro, myofibroblast transformation was induced by transforming growth factor-β1 (TGF-β1) stimulation in primary mouse cardiac fibroblasts (MCFs), and macrophage polarization was induced by lipopolysaccharide (LPS) stimulation in RAW264.7 cells. Western blotting, immunofluorescence, flow cytometry were performed to examine the effects of LMK235. Key findings LMK235 ameliorated cardiac dysfunction post-MI by suppressing fibrosisand inflammation. In MCFs, LMK235 attenuated TGF-β1-induced fibrotic biomarker expression by inhibiting Smad2/3 pathway. In RAW264.7 cells, LMK235 attenuated LPS-induced inflammatory cytokine expression by inhibiting NF-κB pathway. Conclusions LMK235 can attenuate fibrosis post-MI by inhibiting Smad2/3 pathway in cardiac fibroblasts, and attenuate inflammation post-MI by inhibiting NF-κB pathway in macrophages, leading to improved cardiac function.