Abstract 4139434: Promotion of cardiac fibrosis and heart failure by LMCD1

Introduction: Cardiac fibrosis is a typical pathophysiological process associated with ECM deposition, resulting in tissue scaring and organ dysfunction. No specific antifibrotic therapies exist for cardiac fibrosis, mainly because of a limited understanding of disease mechanisms. The activated fibroblasts secrete numerous fibrotic factors and ECM components, thus contributing to the development and progression of cardiac fibrosis. LMCD1 (LIM and cysteine-rich domain) is a member of the LIM family of proteins, which is highly expressed in the heart, and its expression is markedly reduced in heart failure (HF) patients. The role of LMCD1 in cardiac fibrosis remains poorly understood. This study aims to define the role of LMCD in cardiac fibrosis and the molecular mechanisms involved. Methods: The expression of LMCD1 in cardiac myocytes and fibroblasts from adult mouse hearts was determined by western blot analysis. TGF-β1 was used to induce cardiac fibrotic responses in vitro in human cardiac fibroblasts. A loss-of-functional approach was used to determine the functional significance of LMCD1 in cardiac fibrosis. Global LMCD1 KO mice were utilized to determine the functional significance of LIMCD1 in cardiac fibrosis and remodeling in vivo using a murine model of angiotensin II (AngII)-induced fibrosis. Echocardiography was performed to measure the cardiac function. Results: LMCD1 is highly expressed in human CFs, and its expression is markedly upregulated in a time and dose-dependent manner in response to the treatment of TGF-β1. Furthermore, we found that LMCD1 expression was markedly increased in the heart in mice after 4 weeks of Ang II infusion. In human CFs, LMCD1 knockdown significantly prevented TGF-β1-induced expression of fibrotic genes, and LMCD1 KO mice are protected from developing cardiac fibrosis induced by Ang II infusion. Protein and mRNA levels of fibrotic genes were significantly reduced in the heart of LMCD1 KO mice compared to their WT controls. Ang II infusion significantly increased LVAW and LVPW in WT mice, which were markedly attenuated in LMCD1 KO mice. Mechanistically, we found that TGF-β1-induced phosphorylation levels of SMAD2/3 were substantially decreased in LMCD1-deficient CFs. Conclusion: Our findings identified LMCD1 as a critical regulator in promoting cardiac fibrosis by targeting TGF-β1/SMAD signaling and suggested that targeted inhibiting LMCD1 may represent a novel therapeutic strategy to ameliorate cardiac fibrosis.