title: Elevated expression of lipoprotein-associated phospholipase A2 in calcific aortic valve disease: implications for valve mineralization.
abstract: OBJECTIVE
  This study sought to document the presence and role of lipoprotein-associated phospholipase A2 (Lp-PLA2) in calcific aortic valve disease (CAVD).
  
  
  BACKGROUND
  CAVD is a chronic disorder characterized by pathological mineralization and remodeling. Studies have indicated that human CAVD tissues are infiltrated by lipids and that inflammation may play a role in the pathobiology. We hypothesized that Lp-PLA2 (encoded by the PLA2G7 gene) is expressed in CAVD and may play a role in the mineralization of valve interstitial cells.
  
  
  METHODS
  We have documented the expression of the phospholipase A2 family of genes in aortic valves by using a transcriptomic assay. Messenger ribonucleic acid and protein expression were confirmed in aortic valves explanted from 60 patients by quantitative polymerase chain reaction and immunohistochemistry, respectively. The effect of lysophosphatidylcholine, the product of Lp-PLA2 activity, was documented on the mineralization of valve interstitial cell cultures.
  
  
  RESULTS
  Transcriptomic analyses of CAVD and control nonmineralized aortic valves revealed that Lp-PLA2 was increased by 4.2-fold in mineralized aortic valves. Higher expression of Lp-PLA2 in stenotic aortic valves was confirmed by quantitative polymerase chain reaction, immunohistochemistry, and enzymatic Lp-PLA2 activity. The number of Lp-PLA2 transcripts correlated with several indexes of tissue remodeling. In vitro, lysophosphatidylcholine increased the expression of alkaline phosphatase, the ectonucleotide pyrophosphatase/phosphodiesterase 1 enzyme, sodium-dependent phosphate cotransporter 1 (encoded by the SLC20A1 gene), and osteopontin. We then showed that lysophosphatidylcholine-induced mineralization involved ectonucleotidase enzyme as well as apoptosis through a protein-kinase-A-dependent pathway.
  
  
  CONCLUSIONS
  Together, these results demonstrated that Lp-PLA2 is highly expressed in CAVD, and it plays a role in the mineralization of valve interstitial cells. Further work is necessary to document whether Lp-PLA2 could be considered as a novel target in CAVD.
authors.affiliation: Laboratoire d'Études Moléculaires des Valvulopathies, Groupe de Recherche en Valvulopathies, Quebec Heart and Lung Institute/Research Center, Department of Surgery, Laval University, Quebec City, Quebec, Canada.
authors.forename: Ablajan
authors.initials: A
authors.lastname: Mahmut
authors.affiliation: Laboratoire d'Études Moléculaires des Valvulopathies, Groupe de Recherche en Valvulopathies, Quebec Heart and Lung Institute/Research Center, Department of Surgery, Laval University, Quebec City, Quebec, Canada.
authors.forename: Marie-Chloé
authors.initials: MC
authors.lastname: Boulanger
authors.affiliation: Laboratoire d'Études Moléculaires des Valvulopathies, Groupe de Recherche en Valvulopathies, Quebec Heart and Lung Institute/Research Center, Department of Surgery, Laval University, Quebec City, Quebec, Canada.
authors.forename: Diala
authors.initials: D
authors.lastname: El Husseini
authors.affiliation: Laboratoire d'Études Moléculaires des Valvulopathies, Groupe de Recherche en Valvulopathies, Quebec Heart and Lung Institute/Research Center, Department of Surgery, Laval University, Quebec City, Quebec, Canada.
authors.forename: Dominique
authors.initials: D
authors.lastname: Fournier
authors.affiliation: Laboratoire d'Études Moléculaires des Valvulopathies, Groupe de Recherche en Valvulopathies, Quebec Heart and Lung Institute/Research Center, Department of Surgery, Laval University, Quebec City, Quebec, Canada.
authors.forename: Rihab
authors.initials: R
authors.lastname: Bouchareb
authors.affiliation: Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, Quebec, Canada.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Després
authors.affiliation: Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, Quebec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Pibarot
authors.affiliation: Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, Quebec, Canada.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bossé
authors.affiliation: Laboratoire d'Études Moléculaires des Valvulopathies, Groupe de Recherche en Valvulopathies, Quebec Heart and Lung Institute/Research Center, Department of Surgery, Laval University, Quebec City, Quebec, Canada. Electronic address: patrick.mathieu@chg.ulaval.ca.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mathieu
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000096:biosynthesis / Q000235:genetics*; D000368:Aged; D001021:Aortic Valve / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000473:pathology; D000082882:Bicuspid Aortic Valve Disease; D002114:Calcinosis / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D015150:Echocardiography, Doppler; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D006349:Heart Valve Diseases / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics*; D012720:Severity of Illness Index
chemical_list: D012333:RNA, Messenger; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase
keywords: ALP; CAVD; ENPP1; LPC; Lp-PLA2; OPN; PKA; PPi; Pi; Pit-1; VIC; alkaline phosphatase; apoptosis; cAMP; calcific aortic valve disease; cyclic adenosine monophosphate; ectonucleotide pyrophosphatase/phosphodiesterase 1; inorganic phosphate; inorganic pyrophosphate; lipoprotein-associated phospholipase A2; lipoprotein-associated phospholipase A2 (encoded by PLA2G7 gene); lysophosphatidylcholine; osteopontin; ox-LDL; oxidized low-density lipoprotein; protein kinase A; sodium-dependent phosphate cotransporter 1 (encoded by SLC20A1 gene); valve interstitial cells; valve interstitial cells