title: Evidence for active regulation of pro-osteogenic signaling in advanced aortic valve disease.
abstract: OBJECTIVE
  To test the hypothesis that valvular calcium deposition, pro-osteogenic signaling, and function can be altered in mice with advanced aortic valve disease.
  
  
  RESULTS
  "Reversa" mice were given a Western-type diet for 12 months and screened for the presence of aortic valve stenosis. Mice with advanced valve disease were assigned to 1 of 2 groups: (1) those with continued progression for 2 months and (2) those with regression for 2 months, in which lipid lowering was accomplished by a genetic switch. Control mice were normocholesterolemic for 14 months. Mice with advanced valve disease had massive valvular calcification that was associated with increases in bone morphogenetic protein signaling, Wnt/β-catenin signaling, and markers of osteoblastlike cell differentiation. Remarkably, reducing plasma lipids with a genetic switch dramatically reduced markers of pro-osteogenic signaling and significantly reduced valvular calcium deposition. Nevertheless, despite a marked reduction in valvular calcium deposition, valve function remained markedly impaired. Phosphorylated Smad2 levels and myofibroblast activation (indexes of profibrotic signaling) remained elevated.
  
  
  CONCLUSIONS
  Molecular processes that contribute to valvular calcification and osteogenesis remain remarkably labile during the end stages of aortic valve stenosis. Although reductions in valvular calcium deposition were not sufficient to improve valvular function in the animals studied, these findings demonstrate that aortic valve calcification is a remarkably dynamic process that can be modified therapeutically, even in the presence of advanced aortic valve disease.
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Miller
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weiss
authors.forename: Kristine M
authors.initials: KM
authors.lastname: Serrano
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Castaneda
authors.forename: Robert M
authors.initials: RM
authors.lastname: Brooks
authors.forename: Kathy
authors.initials: K
authors.lastname: Zimmerman
authors.forename: Donald D
authors.initials: DD
authors.lastname: Heistad
mesh_terms: D000818:Animals; D001021:Aortic Valve / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D001024:Aortic Valve Stenosis / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D053299:Apolipoprotein B-100 / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002114:Calcinosis / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis; D006937:Hypercholesterolemia / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008055:Lipids / Q000097:blood; D051379:Mice; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis; D010766:Phosphorylation; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D013997:Time Factors; D014463:Ultrasonography; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D053299:Apolipoprotein B-100; D019485:Bone Morphogenetic Proteins; C495267:CTNNB1 protein, mouse; D002352:Carrier Proteins; D008055:Lipids; D011973:Receptors, LDL; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051153:Wnt Proteins; D051176:beta Catenin; C106092:microsomal triglyceride transfer protein