Cadherin-11 Overexpression Induces Extracellular Matrix Remodeling and Calcification in Mature Aortic Valves

作者：Derek C. Sung, Caitlin J. Bowen, Kiran A. Vaidya, Jingjing Zhou, Nikita Chapurin, Andrew K. Recknagel, Bin Zhou, Jonathan H. Chen, Michael I. Kotlikoff, Jonathan Talbot Butcher · 发表于：Arteriosclerosis Thrombosis and Vascular Biology · 年份：2016 · DOI：10.1161/atvbaha.116.307812 · 被引用次数：56 · 研究领域：Caveolin-1 and cellular processes、Connective tissue disorders research、Galectins and Cancer Biology

OBJECTIVE: Calcific aortic valve (AoV) disease is a significant clinical problem for which the regulatory mechanisms are poorly understood. Enhanced cell-cell adhesion is a common mechanism of cellular aggregation, but its role in calcific lesion formation is not known. Cadherin-11 (Cad-11) has been associated with lesion formation in vitro, but its function during adult valve homeostasis and pathogenesis is not known. This study aims to elucidate the specific functions of Cad-11 and its downstream targets, RhoA and Sox9, in extracellular matrix remodeling and AoV calcification. APPROACH AND RESULTS: We conditionally overexpressed Cad-11 in murine heart valves using a novel double-transgenic Nfatc1(Cre);R26-Cad11(TglTg) mouse model. These mice developed hemodynamically significant aortic stenosis with prominent calcific lesions in the AoV leaflets. Cad-11 overexpression upregulated downstream targets, RhoA and Sox9, in the valve interstitial cells, causing calcification and extensive pathogenic extracellular matrix remodeling. AoV interstitial cells overexpressing Cad-11 in an osteogenic environment in vitro rapidly form calcific nodules analogous to in vivo lesions. Molecular analyses revealed upregulation of osteoblastic and myofibroblastic markers. Treatment with a Rho-associated protein kinase inhibitor attenuated nodule formation, further supporting that Cad-11-driven calcification acts through the small GTPase RhoA/Rho-associated protein kinase signaling pathway. CONCLU...