title: ATP acts as a survival signal and prevents the mineralization of aortic valve.
abstract: 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 P2Y(2) 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.
authors.affiliation: Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery, Laval University, Quebec, Canada.
authors.forename: Nancy
authors.initials: N
authors.lastname: Côté
authors.forename: Diala
authors.initials: D
authors.lastname: El Husseini
authors.forename: Andrée
authors.initials: A
authors.lastname: Pépin
authors.forename: Sandra
authors.initials: S
authors.lastname: Guauque-Olarte
authors.forename: Valérie
authors.initials: V
authors.lastname: Ducharme
authors.forename: Pascale
authors.initials: P
authors.lastname: Bouchard-Cannon
authors.forename: Audrey
authors.initials: A
authors.lastname: Audet
authors.forename: Dominique
authors.initials: D
authors.lastname: Fournier
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gaudreault
authors.forename: Habib
authors.initials: H
authors.lastname: Derbali
authors.forename: Marc D
authors.initials: MD
authors.lastname: McKee
authors.forename: Chantale
authors.initials: C
authors.lastname: Simard
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Després
authors.forename: Philippe
authors.initials: P
authors.lastname: Pibarot
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bossé
authors.forename: Patrick
authors.initials: P
authors.lastname: Mathieu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism / Q000502:physiology*; D001021:Aortic Valve / Q000378:metabolism / Q000473:pathology*; D017209:Apoptosis; D002114:Calcinosis / Q000378:metabolism* / Q000473:pathology; D009202:Cardiomyopathies / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism*; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010710:Phosphates / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases / Q000235:genetics* / Q000378:metabolism; D058469:Receptors, Purinergic P2X / Q000235:genetics / Q000378:metabolism; D058470:Receptors, Purinergic P2Y / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000235:genetics / Q000378:metabolism; D046888:Tissue Array Analysis
chemical_list: D010710:Phosphates; D058469:Receptors, Purinergic P2X; D058470:Receptors, Purinergic P2Y; C493586:SLC20A1 protein, human; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D000255:Adenosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases