title: Autotaxin Derived From Lipoprotein(a) and Valve Interstitial Cells Promotes Inflammation and Mineralization of the Aortic Valve.
abstract: BACKGROUND
  Mendelian randomization studies have highlighted that lipoprotein(a) [Lp(a)] was associated with calcific aortic valve disease (CAVD). Lp(a) transports oxidized phospholipids with a high content in lysophosphatidylcholine. Autotaxin (ATX) transforms lysophosphatidylcholine into lysophosphatidic acid. We hypothesized that ATX-lysophosphatidic acid could promote inflammation/mineralization of the aortic valve.
  
  
  RESULTS
  We have documented the expression of ATX in control and mineralized aortic valves. By using different approaches, we have also investigated the role of ATX-lysophosphatidic acid in the mineralization of isolated valve interstitial cells and in a mouse model of CAVD. Enzyme-specific ATX activity was elevated by 60% in mineralized aortic valves in comparison with control valves. Immunohistochemistry studies showed a high level of ATX in mineralized aortic valves, which colocalized with oxidized phospholipids and apolipoprotein(a). We detected a high level of ATX activity in the Lp(a) fraction in circulation. Interaction between ATX and Lp(a) was confirmed by in situ proximity ligation assay. Moreover, we documented that valve interstitial cells also expressed ATX in CAVD. We showed that ATX-lysophosphatidic acid promotes the mineralization of the aortic valve through a nuclear factor κB/interleukin 6/bone morphogenetic protein pathway. In LDLR(-/-)/ApoB(100/100)/IGFII mice, ATX is overexpressed and lysophosphatidic acid promotes a strong deposition of hydroxyapatite of calcium in aortic valve leaflets and accelerates the development of CAVD.
  
  
  CONCLUSIONS
  ATX is transported in the aortic valve by Lp(a) and is also secreted by valve interstitial cells. ATX-lysophosphatidic acid promotes inflammation and mineralization of the aortic valve and thus could represent a novel therapeutic target in CAVD.
authors.affiliation: From Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery (R.B., A.M., M.J.N., M.-C.B., J.-L.L., M.-H.L., F.H., P.M.), Department of Medicine (A.D., P.P., B.J.A., A.M.), Department of Pathology (C.C., S.T., S.P.), and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; and Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada (C.A.S., R.R., M.L.K.).
authors.forename: Rihab
authors.initials: R
authors.lastname: Bouchareb
authors.affiliation: From Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery (R.B., A.M., M.J.N., M.-C.B., J.-L.L., M.-H.L., F.H., P.M.), Department of Medicine (A.D., P.P., B.J.A., A.M.), Department of Pathology (C.C., S.T., S.P.), and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; and Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada (C.A.S., R.R., M.L.K.).
authors.forename: Ablajan
authors.initials: A
authors.lastname: Mahmut
authors.affiliation: From Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery (R.B., A.M., M.J.N., M.-C.B., J.-L.L., M.-H.L., F.H., P.M.), Department of Medicine (A.D., P.P., B.J.A., A.M.), Department of Pathology (C.C., S.T., S.P.), and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; and Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada (C.A.S., R.R., M.L.K.).
authors.forename: Mohamed Jalloul
authors.initials: MJ
authors.lastname: Nsaibia
authors.affiliation: From Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery (R.B., A.M., M.J.N., M.-C.B., J.-L.L., M.-H.L., F.H., P.M.), Department of Medicine (A.D., P.P., B.J.A., A.M.), Department of Pathology (C.C., S.T., S.P.), and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; and Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada (C.A.S., R.R., M.L.K.).
authors.forename: Marie-Chloé
authors.initials: MC
authors.lastname: Boulanger
authors.affiliation: From Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery (R.B., A.M., M.J.N., M.-C.B., J.-L.L., M.-H.L., F.H., P.M.), Department of Medicine (A.D., P.P., B.J.A., A.M.), Department of Pathology (C.C., S.T., S.P.), and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; and Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada (C.A.S., R.R., M.L.K.).
authors.forename: Abdellaziz
authors.initials: A
authors.lastname: Dahou
authors.affiliation: From Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery (R.B., A.M., M.J.N., M.-C.B., J.-L.L., M.-H.L., F.H., P.M.), Department of Medicine (A.D., P.P., B.J.A., A.M.), Department of Pathology (C.C., S.T., S.P.), and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; and Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada (C.A.S., R.R., M.L.K.).
authors.forename: Jamie-Lee
authors.initials: JL
authors.lastname: Lépine
authors.affiliation: From Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery (R.B., A.M., M.J.N., M.-C.B., J.-L.L., M.-H.L., F.H., P.M.), Department of Medicine (A.D., P.P., B.J.A., A.M.), Department of Pathology (C.C., S.T., S.P.), and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; and Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada (C.A.S., R.R., M.L.K.).
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Laflamme
authors.affiliation: From Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery (R.B., A.M., M.J.N., M.-C.B., J.-L.L., M.-H.L., F.H., P.M.), Department of Medicine (A.D., P.P., B.J.A., A.M.), Department of Pathology (C.C., S.T., S.P.), and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; and Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada (C.A.S., R.R., M.L.K.).
authors.forename: Fayez
authors.initials: F
authors.lastname: Hadji
authors.affiliation: From Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery (R.B., A.M., M.J.N., M.-C.B., J.-L.L., M.-H.L., F.H., P.M.), Department of Medicine (A.D., P.P., B.J.A., A.M.), Department of Pathology (C.C., S.T., S.P.), and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; and Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada (C.A.S., R.R., M.L.K.).
authors.forename: Christian
authors.initials: C
authors.lastname: Couture
authors.affiliation: From Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery (R.B., A.M., M.J.N., M.-C.B., J.-L.L., M.-H.L., F.H., P.M.), Department of Medicine (A.D., P.P., B.J.A., A.M.), Department of Pathology (C.C., S.T., S.P.), and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; and Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada (C.A.S., R.R., M.L.K.).
authors.forename: Sylvain
authors.initials: S
authors.lastname: Trahan
authors.affiliation: From Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery (R.B., A.M., M.J.N., M.-C.B., J.-L.L., M.-H.L., F.H., P.M.), Department of Medicine (A.D., P.P., B.J.A., A.M.), Department of Pathology (C.C., S.T., S.P.), and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; and Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada (C.A.S., R.R., M.L.K.).
authors.forename: Sylvain
authors.initials: S
authors.lastname: Pagé
authors.affiliation: From Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery (R.B., A.M., M.J.N., M.-C.B., J.-L.L., M.-H.L., F.H., P.M.), Department of Medicine (A.D., P.P., B.J.A., A.M.), Department of Pathology (C.C., S.T., S.P.), and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; and Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada (C.A.S., R.R., M.L.K.).
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bossé
authors.affiliation: From Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery (R.B., A.M., M.J.N., M.-C.B., J.-L.L., M.-H.L., F.H., P.M.), Department of Medicine (A.D., P.P., B.J.A., A.M.), Department of Pathology (C.C., S.T., S.P.), and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; and Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada (C.A.S., R.R., M.L.K.).
authors.forename: Philippe
authors.initials: P
authors.lastname: Pibarot
authors.affiliation: From Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery (R.B., A.M., M.J.N., M.-C.B., J.-L.L., M.-H.L., F.H., P.M.), Department of Medicine (A.D., P.P., B.J.A., A.M.), Department of Pathology (C.C., S.T., S.P.), and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; and Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada (C.A.S., R.R., M.L.K.).
authors.forename: Corey A
authors.initials: CA
authors.lastname: Scipione
authors.affiliation: From Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery (R.B., A.M., M.J.N., M.-C.B., J.-L.L., M.-H.L., F.H., P.M.), Department of Medicine (A.D., P.P., B.J.A., A.M.), Department of Pathology (C.C., S.T., S.P.), and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; and Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada (C.A.S., R.R., M.L.K.).
authors.forename: Rocco
authors.initials: R
authors.lastname: Romagnuolo
authors.affiliation: From Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery (R.B., A.M., M.J.N., M.-C.B., J.-L.L., M.-H.L., F.H., P.M.), Department of Medicine (A.D., P.P., B.J.A., A.M.), Department of Pathology (C.C., S.T., S.P.), and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; and Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada (C.A.S., R.R., M.L.K.).
authors.forename: Marlys L
authors.initials: ML
authors.lastname: Koschinsky
authors.affiliation: From Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery (R.B., A.M., M.J.N., M.-C.B., J.-L.L., M.-H.L., F.H., P.M.), Department of Medicine (A.D., P.P., B.J.A., A.M.), Department of Pathology (C.C., S.T., S.P.), and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; and Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada (C.A.S., R.R., M.L.K.).
authors.forename: Benoît J
authors.initials: BJ
authors.lastname: Arsenault
authors.affiliation: From Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery (R.B., A.M., M.J.N., M.-C.B., J.-L.L., M.-H.L., F.H., P.M.), Department of Medicine (A.D., P.P., B.J.A., A.M.), Department of Pathology (C.C., S.T., S.P.), and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; and Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada (C.A.S., R.R., M.L.K.).
authors.forename: André
authors.initials: A
authors.lastname: Marette
authors.affiliation: From Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery (R.B., A.M., M.J.N., M.-C.B., J.-L.L., M.-H.L., F.H., P.M.), Department of Medicine (A.D., P.P., B.J.A., A.M.), Department of Pathology (C.C., S.T., S.P.), and Department of Molecular Medicine (Y.B.), Laval University, Québec, Canada; and Department of Chemistry and Biochemistry, University of Windsor, Ontario, Canada (C.A.S., R.R., M.L.K.). patrick.mathieu@chg.ulaval.ca.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mathieu
mesh_terms: D000368:Aged; D000818:Animals; D001021:Aortic Valve / Q000378:metabolism* / Q000473:pathology; D001024:Aortic Valve Stenosis / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D017270:Lipoprotein(a) / Q000096:biosynthesis* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010727:Phosphoric Diester Hydrolases / Q000096:biosynthesis*; D000099189:Lysophospholipase D
chemical_list: D017270:Lipoprotein(a); D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D
keywords: ENPP2; aortic stenosis, calcific; aortic valve stenosis; autotaxin; calcific aortic valve disease; lipoprotein(a); lipoproteins; lysophosphatidic acid; lysophosphatidylcholine