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Notch Signaling in Aortic Valve Development and Disease.


Garg V7,8,9.


Etiology and Morphogenesis of Congenital Heart Disease: From Gene Function and Cellular Interaction to Morphology [Internet]. Tokyo: Springer; 2016. Chapter 53.
2016 Jun 25.

Author information

Department of Pediatric Cardiology, Tokyo Women's Medical University, Tokyo, Japan
Cardiovascular Developmental Biology Center, Medical University of South Carolina Clemson University, Charleston, South Carolina, USA
Department of Pediatrics (Cardiology), Vanderbilt University, Nashville, Tennessee, USA
Pediatrics, Pharmacology and Toxicology, and Bioengineering, University of Louisville, Louisville, Kentucky, USA
Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA
Pediatrics, Division of Pediatric Cardiology, Keio University School of Medicine, Tokyo, Japan
Center for Cardiovascular Research and The Heart Center, Nationwide Children’s Hospital, 700 Children’s Drive Room WB4221, Columbus, OH, 43205, USA
Department of Pediatrics (Cardiology), The Ohio State University, Columbus, OH, USA
Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA


Bicuspid aortic valve (BAV) is the most common type of cardiac malformation with an estimated prevalence of 1 % in the population. BAV results in significant morbidity usually during adulthood due to its association with aortic valve calcification and ascending aortic aneurysms. Mutations in the signaling and transcriptional regulator, NOTCH1, are a cause of bicuspid aortic valve in non-syndromic autosomal dominant human pedigrees. The Notch signaling pathway is critical for multiple cellular processes during both development and disease and is expressed in the developing and adult aortic valve consistent with the cardiac phenotypes identified in affected family members. Recent work has begun to elucidate the molecular mechanisms underlying the link between Notch1 signaling and the development of BAV and valve calcification. Using in vitro approaches, loss of Notch signaling has been shown to contribute to aortic valve calcification via Runx2-, Sox9-, and Bmp2-dependent mechanisms. In addition, Notch1 signaling has been shown to be responsive to nitric oxide signaling during this disease process. A new highly penetrant mouse model of aortic valve disease using Notch1 haploinsufficient mice that are backcrossed in an endothelial nitric oxide synthase (Nos3)-null background was generated. Notch1 and Nos3 compound mutant mice (Notch1+/-;Nos3-/-) display a nearly 100 % incidence of aortic valve malformations, most commonly BAV. The aortic valves of adult mutant mice are thickened and have associated stenosis and regurgitation. Based upon the initial discovery of NOTCH1 mutations in humans with aortic valve disease, subsequent studies have provided significant molecular insights into BAV-associated diseases.

Copyright 2016, The Author(s).

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