title: Transglutaminase inhibitors attenuate vascular calcification in a preclinical model.
abstract: OBJECTIVE
  In vitro, transglutaminase-2 (TG2)-mediated activation of the β-catenin signaling pathway is central in warfarin-induced calcification, warranting inquiry into the importance of this signaling axis as a target for preventive therapy of vascular calcification in vivo.
  
  
  RESULTS
  The adverse effects of warfarin-induced elastocalcinosis in a rat model include calcification of the aortic media, loss of the cellular component in the vessel wall, and isolated systolic hypertension, associated with accumulation and activation of TG2 and activation of β-catenin signaling. These effects of warfarin can be completely reversed by intraperitoneal administration of the TG2-specific inhibitor KCC-009 or dietary supplementation with the bioflavonoid quercetin, known to inhibit β-catenin signaling. Our study also uncovers a previously uncharacterized ability of quercetin to inhibit TG2. Quercetin reversed the warfarin-induced increase in systolic pressure, underlying the functional consequence of this treatment. Molecular analysis shows that quercetin diet stabilizes the phenotype of smooth muscle and prevents its transformation into osteoblastic cells.
  
  
  CONCLUSIONS
  Inhibition of the TG2/β-catenin signaling axis seems to prevent warfarin-induced elastocalcinosis and to control isolated systolic hypertension.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland, School of Medicine, 108 N Greene St, Baltimore, MD 21021, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Beazley
authors.forename: Derek
authors.initials: D
authors.lastname: Banyard
authors.forename: Florence
authors.initials: F
authors.lastname: Lima
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Deasey
authors.forename: Dmitry I
authors.initials: DI
authors.lastname: Nurminsky
authors.forename: Mikhail
authors.initials: M
authors.lastname: Konoplyannikov
authors.forename: Maria V
authors.initials: MV
authors.lastname: Nurminskaya
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D001018:Aortic Diseases / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D010766:Phosphorylation; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011794:Quercetin / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D061205:Vascular Calcification / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D014859:Warfarin; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495268:Ctnnb1 protein, rat; D004791:Enzyme Inhibitors; D007555:Isoxazoles; C510621:KCC 009; C000717609:Tgm2 protein, rat; D051176:beta Catenin; D014859:Warfarin; D011794:Quercetin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D019204:GTP-Binding Proteins