ATP acts as a survival signal and prevents the mineralization of aortic valve

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• 作者：Nancy Cô ; té ; ^a ; ¹ ; Diala El Husseini^a ; ¹ ; André ; e Pé ; pin^a ; Sandra Guauque-Olarte^b ; Valé ; rie Ducharme^a ; Pascale Bouchard-Cannon^a ; Audrey Audet^a ; Dominique Fournier^a ; Nathalie Gaudreault^b ; Habib Derbali^a ; Marc D. McKee^d ; Chantale Simard^e ; Jean-Pierre Despré ; s^f ; ^g ; Philippe Pibarot^b ; Yohan Bossé ; ^b ; ^c ; Patrick Mathieu^a ; ^{patrick.mathieu@chg.ulaval.ca}
• 关键词：Calcific aortic valve disease ; Aortic stenosis ; P2Y2 receptor ; PI3K ; Ectonucleotidase ; ENPP1 ; ATP ; Mineralization
• 刊名：Journal of Molecular and Cellular Cardiology
• 出版年：2012
• 期刊代码：171_00222828
• 类别：bio
• 出版时间：May, 2012
• 卷：52
• 期：5
• 页码：1191-1202
• 文件大小：1549 K

摘要

Calcific aortic valve disease (CAVD) is a disorder related to progressive mineralization of valvular tissue that is a leading cause of heart disease. Thus far, there is no medical treatment to prevent the mineralization of aortic valves. It is generally thought that pathologic mineralization is linked to apoptosis of vascular cells. However, the role of apoptosis during mineralization as well as the survival signals for valvular interstitial cells (VICs), the main cellular component of aortic valves, remains to be identified. Here, through several lines of evidence, we show that bioavailability of extracellular ATP is a signal which determines survival or apoptosis of VICs and, in doing so, plays a major role in the development of CAVD. Specifically, in CAVD and in VIC cultures undergoing mineralization, we found a high level of the ectonucleotidase ENPP1. In addition, a genetic polymorphism in the intron 9 of the ENPP1 gene was associated with CAVD in a case-control cohort as well as with mRNA expression levels of ENPP1 in aortic valves. A high level of ENPP1 in CAVD promoted apoptosis-mediated mineralization of VICs by depleting the extracellular pool of ATP. We then documented that release of ATP by VICs promoted cell survival via the P2Y₂ receptor and the PI3K/Akt signaling pathway. Hence, our results show that level of ENPP1 modulates extracellular concentration of ATP, which is an important survival signal for VICs. These findings may help to develop novel pharmacological treatment for CAVD.