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http://purl.uniprot.org/citations/26023079http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/26023079http://www.w3.org/2000/01/rdf-schema#comment"

Objective

Calcific aortic valve disease (CAVD) is a significant cardiovascular disorder, and controversy exists as to whether it is primarily a dystrophic or osteogenic process in vivo. In this study, we sought to clarify the mechanism of CAVD by assessing a genetic mutation, Notch1 heterozygosity, which leads to CAVD with 100% penetrance in humans.

Approach and results

Murine immortalized Notch1(+/-) aortic valve interstitial cells (AVICs) were isolated and expanded in vitro. Molecular signaling of wild-type and Notch1(+/-) AVICs were compared to identify changes in pathways that have been linked to CAVD-transforming growth factor-β1/bone morphogenetic protein, mitogen-activated protein kinase, and phosphoinositide 3-kinase/protein kinase B-and assessed for calcification potential. Additionally, AVIC mechanobiology was studied in a physiologically relevant, dynamic mechanical environment (10% cyclic strain) to investigate differences in responses between the cell types. We found that Notch1(+/-) AVICs resembled a myofibroblast-like phenotype expressing higher amounts of cadherin-11, a known mediator of dystrophic calcification, and decreased Runx2, a known osteogenic marker. We determined that cadherin-11 expression is regulated by Akt activity, and inhibition of Akt phosphorylation significantly reduced cadherin-11 expression. Moreover, in the presence of cyclic strain, Notch1(+/-) AVICs exhibited significantly upregulated phosphorylation of Akt at Ser473 and smooth muscle α-actin expression, indicative of a fully activated myofibroblast. Finally, these Notch1-mediated alterations led to enhanced dystrophic calcific nodule formation.

Conclusions

This study presents novel insights in our understanding of Notch1-mediated CAVD by demonstrating that the mutation leads to AVICs that are fully activated myofibroblasts, resulting in dystrophic, but not osteogenic, calcification."xsd:string
http://purl.uniprot.org/citations/26023079http://purl.org/dc/terms/identifier"doi:10.1161/atvbaha.114.305095"xsd:string
http://purl.uniprot.org/citations/26023079http://purl.uniprot.org/core/author"Chen J."xsd:string
http://purl.uniprot.org/citations/26023079http://purl.uniprot.org/core/author"Brown C.B."xsd:string
http://purl.uniprot.org/citations/26023079http://purl.uniprot.org/core/author"Baldwin H.S."xsd:string
http://purl.uniprot.org/citations/26023079http://purl.uniprot.org/core/author"Huppert S.S."xsd:string
http://purl.uniprot.org/citations/26023079http://purl.uniprot.org/core/author"Merryman W.D."xsd:string
http://purl.uniprot.org/citations/26023079http://purl.uniprot.org/core/author"Ryzhova L.M."xsd:string
http://purl.uniprot.org/citations/26023079http://purl.uniprot.org/core/author"Sewell-Loftin M.K."xsd:string
http://purl.uniprot.org/citations/26023079http://purl.uniprot.org/core/date"2015"xsd:gYear
http://purl.uniprot.org/citations/26023079http://purl.uniprot.org/core/name"Arterioscler Thromb Vasc Biol"xsd:string
http://purl.uniprot.org/citations/26023079http://purl.uniprot.org/core/pages"1597-1605"xsd:string
http://purl.uniprot.org/citations/26023079http://purl.uniprot.org/core/title"Notch1 Mutation Leads to Valvular Calcification Through Enhanced Myofibroblast Mechanotransduction."xsd:string
http://purl.uniprot.org/citations/26023079http://purl.uniprot.org/core/volume"35"xsd:string
http://purl.uniprot.org/citations/26023079http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/26023079
http://purl.uniprot.org/citations/26023079http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/26023079
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http://purl.uniprot.org/uniprot/#_Q01705-mappedCitation-26023079http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/26023079
http://purl.uniprot.org/uniprot/#_Q8BY39-mappedCitation-26023079http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/26023079
http://purl.uniprot.org/uniprot/#_P31749-mappedCitation-26023079http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/26023079
http://purl.uniprot.org/uniprot/Q01705http://purl.uniprot.org/core/mappedCitationhttp://purl.uniprot.org/citations/26023079
http://purl.uniprot.org/uniprot/Q8BY39http://purl.uniprot.org/core/mappedCitationhttp://purl.uniprot.org/citations/26023079
http://purl.uniprot.org/uniprot/P31749http://purl.uniprot.org/core/mappedCitationhttp://purl.uniprot.org/citations/26023079
http://purl.uniprot.org/uniprot/A2AIX5http://purl.uniprot.org/core/mappedCitationhttp://purl.uniprot.org/citations/26023079
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