title: Osteoprotegerin inhibits aortic valve calcification and preserves valve function in hypercholesterolemic mice.
abstract: BACKGROUND
  There are no rigorously confirmed effective medical therapies for calcific aortic stenosis. Hypercholesterolemic Ldlr (-/-) Apob (100/100) mice develop calcific aortic stenosis and valvular cardiomyopathy in old age. Osteoprotegerin (OPG) modulates calcification in bone and blood vessels, but its effect on valve calcification and valve function is not known.
  
  
  OBJECTIVE
  To determine the impact of pharmacologic treatment with OPG upon aortic valve calcification and valve function in aortic stenosis-prone hypercholesterolemic Ldlr (-/-) Apob (100/100) mice.
  
  
  METHODS
  Young Ldlr (-/-) Apob (100/100) mice (age 2 months) were fed a Western diet and received exogenous OPG or vehicle (N = 12 each) 3 times per week, until age 8 months. After echocardiographic evaluation of valve function, the aortic valve was evaluated histologically. Older Ldlr (-/-) Apob (100/100) mice were fed a Western diet beginning at age 2 months. OPG or vehicle (N = 12 each) was administered from 6 to 12 months of age, followed by echocardiographic evaluation of valve function, followed by histologic evaluation.
  
  
  RESULTS
  In Young Ldlr (-/-) Apob (100/100) mice, OPG significantly attenuated osteogenic transformation in the aortic valve, but did not affect lipid accumulation. In Older Ldlr (-/-) Apob (100/100) mice, OPG attenuated accumulation of the osteoblast-specific matrix protein osteocalcin by ∼80%, and attenuated aortic valve calcification by ∼ 70%. OPG also attenuated impairment of aortic valve function.
  
  
  CONCLUSIONS
  OPG attenuates pro-calcific processes in the aortic valve, and protects against impairment of aortic valve function in hypercholesterolemic aortic stenosis-prone Ldlr (-/-) Apob (100/100) mice.
authors.affiliation: Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America. robert-weiss@uiowa.edu
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weiss
authors.forename: Donald D
authors.initials: DD
authors.lastname: Lund
authors.forename: Yi
authors.initials: Y
authors.lastname: Chu
authors.forename: Robert M
authors.initials: RM
authors.lastname: Brooks
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Zimmerman
authors.forename: Ramzi
authors.initials: R
authors.lastname: El Accaoui
authors.forename: Melissa K
authors.initials: MK
authors.lastname: Davis
authors.forename: Georges P
authors.initials: GP
authors.lastname: Hajj
authors.forename: M Bridget
authors.initials: MB
authors.lastname: Zimmerman
authors.forename: Donald D
authors.initials: DD
authors.lastname: Heistad
mesh_terms: D000367:Age Factors; D000818:Animals; D001021:Aortic Valve / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053299:Apolipoprotein B-100 / Q000235:genetics; D002114:Calcinosis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006937:Hypercholesterolemia / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007267:Injections; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010012:Osteogenesis / Q000187:drug effects; D053244:Osteoprotegerin / Q000494:pharmacology*; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D014463:Ultrasonography
chemical_list: D053299:Apolipoprotein B-100; D053244:Osteoprotegerin; D011973:Receptors, LDL