Notch1 represses osteogenic pathways in aortic valve cells

Gladstone Institute of Cardiovascular Disease and Departments of Pediatrics, University of California, San Francisco, CA 94158, USA.
Journal of Molecular and Cellular Cardiology (Impact Factor: 5.22). 09/2009; 47(6):828-34. DOI: 10.1016/j.yjmcc.2009.08.008
Source: PubMed

ABSTRACT Calcific aortic stenosis is the third leading cause of adult heart disease and the most common form of acquired valvular disease in developed countries. However, the molecular pathways leading to calcification are poorly understood. We reported two families in which heterozygous mutations in NOTCH1 caused bicuspid aortic valve and severe aortic valve calcification. NOTCH1 is part of a highly conserved signaling pathway involved in cell fate decisions, cell differentiation, and cardiac valve formation. In this study, we examined the mechanism by which NOTCH1 represses aortic valve calcification. Heterozygous Notch1-null (Notch1(+/)(-)) mice had greater than fivefold more aortic valve calcification than age- and sex-matched wildtype littermates. Inhibition of Notch signaling in cultured sheep aortic valve interstitial cells (AVICs) also increased calcification more than fivefold and resulted in gene expression typical of osteoblasts. We found that Notch1 normally represses the gene encoding bone morphogenic protein 2 (Bmp2) in murine aortic valves in vivo and in aortic valve cells in vitro. siRNA-mediated knockdown of Bmp2 blocked the calcification induced by Notch inhibition in AVICs. These findings suggest that Notch1 signaling in aortic valve cells represses osteoblast-like calcification pathways mediated by Bmp2.

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    • "In addition, Notch1 haploinsufficient mice have been shown to develop aortic valve calcification [18] [19]. Using an established aortic valve interstitial cell (AVIC) culture system that spontaneously calcifies in vitro, it has been shown that inhibition of Notch signaling in AVICs accelerates the calcification process, potentially by regulating Bmp2 signaling and Sox9 [18] [19] [20]. However, the mechanisms by which Notch1 signaling is regulated in the process of CAVD have not been investigated. "
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    ABSTRACT: The mature aortic valve is composed of a structured trilaminar extracellular matrix that is interspersed with aortic valve interstitial cells (AVICs) and covered by endothelium. Dysfunction of the valvular endothelium initiates calcification of neighboring AVICs leading to calcific aortic valve disease (CAVD). The molecular mechanism by which endothelial cells communicate with AVICs and cause disease is not well understood. Using a co-culture assay, we show that endothelial cells secrete a signal to inhibit calcification of AVICs. Gain or loss of nitric oxide (NO) prevents or accelerates calcification of AVICs, respectively, suggesting that the endothelial cell-derived signal is NO. Overexpression of Notch1, which is genetically linked to human CAVD, retards the calcification of AVICs that occurs with NO inhibition. In AVICs, NO regulates the expression of Hey1, a downstream target of Notch1, and alters nuclear localization of Notch1 intracellular domain. Finally, Notch1 and NOS3 (endothelial NO synthase) display an in vivo genetic interaction critical for proper valve morphogenesis and the development of aortic valve disease. Our data suggests that endothelial cell-derived NO is a regulator of Notch1 signaling in AVICs in the development of the aortic valve and adult aortic valve disease.
    Journal of Molecular and Cellular Cardiology 04/2013; 60(1). DOI:10.1016/j.yjmcc.2013.04.001 · 5.22 Impact Factor
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    • "In the last couple of years, different groups have tried to shed light on the molecular mechanism of aortic valve calcification. Nigam and Srivastava reported that inhibition of Bmp2 blocked calcification of murine aortic valves in vivo and in vitro, suggesting that Notch1 represses Bmp2 within the aortic valve [50]. In addition, Acharya et al. discovered that inhibition of Notch1 in an in vitro model of aortic valve calcification was prevented by the addition of Sox9, indicating that Notch1 regulates aortic valve calcification through a Sox-9-dependent pathway [51]. "
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    ABSTRACT: Bicuspid aortic valve (BAV) is the most common congenital heart defect, affecting 1-2% of the population. It is generally diagnosed late in adulthood when deterioration of the abnormal leaflet becomes clinically evident. BAV patients have an increased risk of developing serious complications, including stenosis, regurgitation, endocarditis, dilation of the aorta, aortic dissection, and aneurysm. BAV is a heritable trait, but the genetic basis underlying this cardiac malformation remains poorly understood. In the last decade, thanks to studies in animal models as well as genetic and biochemical approaches, a large number of genes that play important roles in heart development have been identified. These discoveries provided valuable insight into cardiac morphogenesis and uncovered congenital-heart-disease-causing genes. This paper will summarize the current knowledge of valve morphogenesis as well as our current understanding of the genetic pathways involved in BAV formation. The impact of these advances on human health including diagnosis of BAV and prevention of cardiovascular complications in individuals with BAV or with a family history of BAV is also discussed.
    06/2012; 2012:180297. DOI:10.1155/2012/180297
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    • "Heterozygous Notch1 mutant mice do not show BAV but develop signs of aortic valve calcification when fed a western diet, although unlike human patients, they do not develop stenosis (Nigam and Srivastava, 2009). In similar experiments, heterozygous RBPJk or Notch1 mice were fed a high-fat diet supplemented with vitamin D (Nus et al., 2011). "
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    ABSTRACT: The Notch pathway is a crucial cell-fate regulator in the developing heart. Attention in the past centered on Notch function in cardiomyocytes. However, recent advances demonstrate that region-specific endocardial Notch activity orchestrates the patterning and morphogenesis of cardiac chambers and valves through regulatory interaction with multiple myocardial and neural crest signals. Notch also regulates cardiomyocyte proliferation and differentiation during ventricular chamber development and is required for coronary vessel specification. Here, we review these data and highlight disease connections, including evidence that Notch-Hey-Bmp2 interplay impacts adult heart valve disease and that Notch contributes to cardiac arrhythmia and pre-excitation syndromes.
    Developmental Cell 02/2012; 22(2):244-54. DOI:10.1016/j.devcel.2012.01.014 · 10.37 Impact Factor
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