title: Carbonic anhydrase XII in valve interstitial cells promotes the regression of calcific aortic valve stenosis.
abstract: OBJECTIVE
  Calcific aortic valve stenosis (CAVS) is the most common heart valve disease. In the present work we sought to determine the reversibility of mineralization in the aortic valve.
  
  
  RESULTS
  By using in vitro analyses we found that valve interstitial cells (VICs) have the ability to resorb minerals. We documented that agonist of P2Y2 receptor (P2Y2R) promoted the expression of carbonic anhydrase XII (CAXII) at the cell membrane of VICs, whereby minerals are resorbed. P2Y2R-mediated mineral resorption was corroborated by using mouse VICs isolated from wild type and P2Y2R(-/-) mice. Measurements of extracellular pH (pHe) by using core-shell nanosensors revealed that P2Y2R-mediated CAXII export to the cell membrane led to an acidification of extracellular space, whereby minerals are resorbed. In vivo, we next treated LDLR(-/-)/ApoB(100/100)/IGF2 mice, which had developed CAVS under a high-fat/high-sucrose diet for 8 months, with 2-thioUTP (a P2Y2R agonist) or saline for the next 2 months. The administration of 2-thioUTP (2mg/kg/day i.p.) reduced the mineral volume in the aortic valve measured with serial microCT analyses, which improved hemodynamics and reduced left ventricular hypertrophy (LVH). Examination of leaflets at necropsy confirmed a lower level of mineralization and fibrosis along with higher levels of CAXII in mice under 2-thioUTP. In another series of experiment, the administration of acetazolamide (a CA inhibitor) prevented the acidification of leaflets and the regression of CAVS induced by 2-thioUTP in LDLR(-/-)/ApoB(100/100)/IGF2 mice.
  
  
  CONCLUSIONS
  P2Y2R-mediated expression of CAXII by VICs acidifies the extracellular space and promotes the regression of CAVS.
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, Québec, Canada.
authors.forename: Rihab
authors.initials: R
authors.lastname: Bouchareb
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, Québec, Canada.
authors.forename: Nancy
authors.initials: N
authors.lastname: Côté
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, Québec, Canada.
authors.lastname: Marie-Chloé-Boulanger
authors.affiliation: Department of Medicine, Laval University, Québec, Canada.
authors.forename: Khai
authors.initials: K
authors.lastname: Le Quang
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, Québec, Canada.
authors.forename: Diala
authors.initials: D
authors.lastname: El Husseini
authors.affiliation: The Center for Optics, Photonics and Lasers (COPL), Department of Physics, Laval University, Québec, Canada.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Asselin
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, Québec, Canada.
authors.forename: Fayez
authors.initials: F
authors.lastname: Hadji
authors.affiliation: Department of Medicine, Laval University, Québec, Canada.
authors.forename: Dominic
authors.initials: D
authors.lastname: Lachance
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, Québec, Canada.
authors.forename: Elnur Elyar
authors.initials: EE
authors.lastname: Shayhidin
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, Québec, Canada.
authors.forename: Ablajan
authors.initials: A
authors.lastname: Mahmut
authors.affiliation: Department of Medicine, Laval University, Québec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Pibarot
authors.affiliation: Department of Molecular Medicine, Laval University, Québec, Canada.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bossé
authors.affiliation: The Center for Optics, Photonics and Lasers (COPL), Department of Physics, Laval University, Québec, Canada.
authors.forename: Younes
authors.initials: Y
authors.lastname: Messaddeq
authors.affiliation: The Center for Optics, Photonics and Lasers (COPL), Department of Physics, Laval University, Québec, Canada.
authors.forename: Denis
authors.initials: D
authors.lastname: Boudreau
authors.affiliation: Department of Medicine, Laval University, Québec, Canada.
authors.forename: André
authors.initials: A
authors.lastname: Marette
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, Québec, Canada. Electronic address: patrick.mathieu@chg.ulaval.ca.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mathieu
mesh_terms: D000818:Animals; D001024:Aortic Valve Stenosis / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D002114:Calcinosis / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D002256:Carbonic Anhydrases / Q000378:metabolism*; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000378:metabolism; D006351:Heart Valves / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008903:Minerals / Q000378:metabolism; D058912:Purinergic P2Y Receptor Agonists / Q000494:pharmacology; D058473:Receptors, Purinergic P2Y2 / Q000378:metabolism
chemical_list: D008903:Minerals; D058912:Purinergic P2Y Receptor Agonists; D058473:Receptors, Purinergic P2Y2; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII
keywords: Calcific aortic stenosis; Calcific aortic valve disease; Carbonic anhydrase XII; Mineral regression; Mineral resorption; P2Y(2) receptor