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http://purl.uniprot.org/citations/27312222http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/27312222http://www.w3.org/2000/01/rdf-schema#comment"

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.

Conclusions

This study identifies one of the underlying molecular mechanisms of heart valve calcification and demonstrates that overexpression of Cad-11 upregulates RhoA and Sox9 to induce calcification and extracellular matrix remodeling in adult AoV pathogenesis. The findings provide a potential molecular target for clinical treatment."xsd:string
http://purl.uniprot.org/citations/27312222http://purl.org/dc/terms/identifier"doi:10.1161/atvbaha.116.307812"xsd:string
http://purl.uniprot.org/citations/27312222http://purl.uniprot.org/core/author"Chen J."xsd:string
http://purl.uniprot.org/citations/27312222http://purl.uniprot.org/core/author"Zhou J."xsd:string
http://purl.uniprot.org/citations/27312222http://purl.uniprot.org/core/author"Zhou B."xsd:string
http://purl.uniprot.org/citations/27312222http://purl.uniprot.org/core/author"Butcher J.T."xsd:string
http://purl.uniprot.org/citations/27312222http://purl.uniprot.org/core/author"Bowen C.J."xsd:string
http://purl.uniprot.org/citations/27312222http://purl.uniprot.org/core/author"Kotlikoff M."xsd:string
http://purl.uniprot.org/citations/27312222http://purl.uniprot.org/core/author"Recknagel A."xsd:string
http://purl.uniprot.org/citations/27312222http://purl.uniprot.org/core/author"Sung D.C."xsd:string
http://purl.uniprot.org/citations/27312222http://purl.uniprot.org/core/author"Chapurin N."xsd:string
http://purl.uniprot.org/citations/27312222http://purl.uniprot.org/core/author"Vaidya K.A."xsd:string
http://purl.uniprot.org/citations/27312222http://purl.uniprot.org/core/date"2016"xsd:gYear
http://purl.uniprot.org/citations/27312222http://purl.uniprot.org/core/name"Arterioscler Thromb Vasc Biol"xsd:string
http://purl.uniprot.org/citations/27312222http://purl.uniprot.org/core/pages"1627-1637"xsd:string
http://purl.uniprot.org/citations/27312222http://purl.uniprot.org/core/title"Cadherin-11 Overexpression Induces Extracellular Matrix Remodeling and Calcification in Mature Aortic Valves."xsd:string
http://purl.uniprot.org/citations/27312222http://purl.uniprot.org/core/volume"36"xsd:string
http://purl.uniprot.org/citations/27312222http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/27312222
http://purl.uniprot.org/citations/27312222http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/27312222
http://purl.uniprot.org/uniprot/#_P55288-mappedCitation-27312222http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/27312222
http://purl.uniprot.org/uniprot/#_Q8C7Q6-mappedCitation-27312222http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/27312222
http://purl.uniprot.org/uniprot/Q8C7Q6http://purl.uniprot.org/core/mappedCitationhttp://purl.uniprot.org/citations/27312222
http://purl.uniprot.org/uniprot/P55288http://purl.uniprot.org/core/mappedCitationhttp://purl.uniprot.org/citations/27312222