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Notch1 Mutation Leads to Valvular Calcification Through Enhanced Myofibroblast Mechanotransduction

Notch1 Mutation Leads to Valvular Calcification Through Enhanced Myofibroblast Mechanotransduction 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Arteriosclerosis, Thrombosis, and Vascular Biology Wolters Kluwer Health

Notch1 Mutation Leads to Valvular Calcification Through Enhanced Myofibroblast Mechanotransduction

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References (59)

Copyright
© 2015 American Heart Association, Inc.
Subject
19; 89; 138; Basic Sciences
ISSN
1079-5642
eISSN
1524-4636
DOI
10.1161/ATVBAHA.114.305095
pmid
26023079
Publisher site
See Article on Publisher Site

Abstract

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.

Journal

Arteriosclerosis, Thrombosis, and Vascular BiologyWolters Kluwer Health

Published: Jul 1, 2015

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