Altered DNA Methylation of Long Noncoding RNA
            <i>H19</i>
            in Calcific Aortic Valve Disease Promotes Mineralization by Silencing
            <i>NOTCH1</i>

Hadji, Fayez; Boulanger, Marie-Chloé; Guay, Simon-Pierre; Gaudreault, Nathalie; Amellah, Soumiya; Mkannez, G.; Bouchareb, Rihab; Marchand, Joël Tremblay; Nsaibia, Mohamed Jalloul; Guauque-Olarte, Sandra; Pîbarot, Philippe; Bouchard, Luigi; Bossé, Yohan; Mathieu, Patrick

doi:10.1161/circulationaha.116.023116

Cited by 189 publications

(152 citation statements)

References 40 publications

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“…Silencing H19 inhibits RUNX2 and BMP2, classic markers of osteogenic calcification, and reduced mineralization, while overexpression had the opposite effects. Furthermore, it was found that H19 overexpression reduced activity on the NOTCH1 promoter, identifying H19 as a novel suppressor of NOTCH1 and therapeutic target in CAVD [42]. …”

Section: Molecular Pathways For Aortic Valve Calcificationmentioning

confidence: 99%

“…Hemodynamic shear stress caused an increase in anti-osteogenic and anti-inflammatory networks in wildtype, but not NOTCH1 +/− endothelial cells, indicating that endothelial NOTCH1 mediates the protective effects of shear stress [43]. The authors also found a discrepancy in H3K27ac at NOTCH1-bound enhancers, which correlated with an alteration in the downstream transcriptome, suggesting that this mutation alters the epigenetic profile in endothelial cells [42]. In another related study, the same group discovered that Matrix Gla Protein (MGP) is a direct target of NOTCH1 in human aortic VECs and responds to shear stress in a NOTCH1-dependent manner.…”

Section: Molecular Pathways For Aortic Valve Calcificationmentioning

confidence: 99%

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Genetic basis of aortic valvular disease

Koenig

Lincoln

Garg

2017

Current Opinion in Cardiology

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Purpose of Review Aortic valve disease is relatively common and encompasses both congenital and acquired forms. Bicuspid aortic valve (BAV) is the most common type of cardiac malformation and predisposes to the development of calcific aortic valve disease (CAVD). Since the description of the link between NOTCH1 and BAV and CAVD approximately a decade ago, there have been significant advances in the genetic and molecular understanding of these diseases. Recent findings Recent work has defined the congenital cardiac phenotypes linked to mutations in NOTCH1 and in addition, novel etiologic genes for BAV have been discovered using new genetic technologies in humans. Furthermore, several mouse models of BAV have been described defining the role of endothelial Notch1 in aortic valve morphogenesis while others have implicated new genes. These murine models along with other cell-based studies have led to molecular insights in the pathogenesis of CAVD. Summary These findings provide important insights into the molecular and genetic basis of aortic valve malformations, including BAV, specifically highlighting the etiologic role of endothelial cells. In addition, numerous investigations in the mechanisms of CAVD demonstrate the importance of developmental origins and signaling pathways as well as communication between valve endothelial cells and the underlying interstitial cells in valve disease onset and progression.

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Section: Molecular Pathways For Aortic Valve Calcificationmentioning

confidence: 99%

Section: Molecular Pathways For Aortic Valve Calcificationmentioning

confidence: 99%

Genetic basis of aortic valvular disease

Koenig

Lincoln

Garg

2017

Current Opinion in Cardiology

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“…Understanding the molecular mechanism of warfarin-induced aortic valve calcification is important to develop preventives or therapeutics. It has recently been shown that the long noncoding RNA (lncRNA) H19 in aortic valve interstitial cells (AVICs) 4 regulates Notch1 by preventing recruitment of p53 to the Notch1 promoter and thereby promotes calcification (10) indicating that p53 functions a transcription factor during AVIC calcification. Calcification of vascular smooth muscle cells can be induced with a 10 μ M therapeutic level of warfarin (11,12).…”

mentioning

confidence: 99%

Low-level overexpression of p53 promotes warfarin-induced calcification of porcine aortic valve interstitial cells by activating Slug gene transcription

Gao¹,

Ji²,

Lü³

et al. 2018

Journal of Biological Chemistry

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The most frequently used oral anti-coagulant warfarin has been implicated in inducing calcification of aortic valve interstitial cells (AVICs), while the mechanism is not fully understood. The low-level activation of p53 is found to be involved in osteogenic transdifferentiation and calcification of AVICs. Whether p53 participating in warfarin-induced AVIC calcification remains unknown. In this study, we investigated the role of low-level p53 overexpression in warfarin-induced porcine AVIC (pAVIC) calcification.Immunostaining, quantitative PCR and western blotting revealed that p53 was expressed in human and pAVICs and that p53 expression was slightly increased in calcific human aortic valves compared with non-calcific valves. TUNEL staining indicated that apoptosis slightly increased in calcific aortic valves than in non-calcific valves. Warfarin treatment led to lowlevel increase of p53 mRNA and protein both in pAVICs and mouse aortic valves. Low-level overexpression of p53 in pAVICs via an adenovirus vector did not affect pAVIC apoptosis, but promoted warfarin-induced calcium deposition and expression of osteogenic markers. shRNAmediated p53 knockdown attenuated the pAVIC calcium deposition and osteogenic marker expression. Moreover, ChIP and luciferase assays showed that p53 was recruited to the slug promoter and activated slug expression in calcific pAVICs. Of note, overexpression of Slug increased osteogenic marker Runx2 expression, but not pAVIC calcium deposition, and Slug knockdown attenuated pAVIC calcification and p53-mediated pAVIC calcium deposition and expression of osteogenic markers. In conclusion, we found that p53 plays an important role in warfarin induced pAVIC calcification and increased slug transcription by p53 is required for p53-mediated pAVIC calcification.The tumor suppressor p53 plays important roles in cell cycle regulation, apoptosis, and DNA p53 and aortic valve interstitial cell calcification 2 damage (1), as well as in osteoblastic differentiation and bone development. Deletion of the p53 inhibitor MDM2 in osteoblast lineage cells leads to increased p53 production and suppression of bone organogenesis and homeostasis, whereas deletion of p53 accelerates osteoblast cell differentiation and bone formation (2,3). In addition, using p53 knockout mice with chronic kidney disease, Li, KL, et al. showed that p53 negatively regulates osteogenic differentiation of vascular smooth muscle cells and aortic calcification suggesting the p53 is involved in pathological tissue calcification (4).The vitamin K antagonist, warfarin, is the most frequently used oral anti-coagulant to treat thromboprophylaxis in the presence of atrial fibrillation or a mechanical prosthetic heart valve. Recently, human and animal studies have implicated warfarin use with vascular and valvular calcification. Long-term warfarin treatment impairs vitamin K-dependent modification of many proteins, including matrix gla protein (MGP), inhibits the bone morphogenetic protein 2 (BMP2) and bone morphogenetic protein...

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“…That causal link has been elusive until the recent and impressive work by Hadjj et al, in this issue of Circulation , demonstrated that the promoter region of the long non-coding (lnc) RNA H19 is hypomethylated in patients with CAVD. 3 This hypomethylation, in turn, increases H19 expression in the valve interstitial cells (VICs) where it prevents NOTCH1 transcription by seemingly blocking or outcompeting p53’s recruitment to the NOTCH1 promoter. Thus, H19 appears to be the missing link (or lncRNA, if you will) connecting NOTCH1 to idiopathic CAVD.…”

mentioning

confidence: 99%

“…13 CDH11 overexpression causes CAVD in mice 14 and has been found to be upregulated in cases of human idiopathic CAVD (Figure). 15 Additionally, Hadjj et al showed that knockdown of H19 decreased CDH11 by ~30% in human VICs cultured in osteogenic medium (Supplemental Figure 1 in 3 ). Interestingly, CDH11 transcription was not increased by osteogenic medium, suggesting that H19 expression may directly affect CDH11 through repression of NOTCH1 .…”

mentioning

confidence: 99%