title: Fibrotic Aortic Valve Stenosis in Hypercholesterolemic/Hypertensive Mice.
abstract: OBJECTIVE
  Hypercholesterolemia and hypertension are associated with aortic valve stenosis (AVS) in humans. We have examined aortic valve function, structure, and gene expression in hypercholesterolemic/hypertensive mice.
  
  
  RESULTS
  Control, hypertensive, hypercholesterolemic (Apoe(-/-)), and hypercholesterolemic/hypertensive mice were studied. Severe aortic stenosis (echocardiography) occurred only in hypercholesterolemic/hypertensive mice. There was minimal calcification of the aortic valve. Several structural changes were identified at the base of the valve. The intercusp raphe (or seam between leaflets) was longer in hypercholesterolemic/hypertensive mice than in other mice, and collagen fibers at the base of the leaflets were reoriented to form a mesh. In hypercholesterolemic/hypertensive mice, the cusps were asymmetrical, which may contribute to changes that produce AVS. RNA sequencing was used to identify molecular targets during the developmental phase of stenosis. Genes related to the structure of the valve were identified, which differentially expressed before fibrotic AVS developed. Both RNA and protein of a profibrotic molecule, plasminogen activator inhibitor 1, were increased greatly in hypercholesterolemic/hypertensive mice.
  
  
  CONCLUSIONS
  Hypercholesterolemic/hypertensive mice are the first model of fibrotic AVS. Hypercholesterolemic/hypertensive mice develop severe AVS in the absence of significant calcification, a feature that resembles AVS in children and some adults. Structural changes at the base of the valve leaflets include lengthening of the raphe, remodeling of collagen, and asymmetry of the leaflets. Genes were identified that may contribute to the development of fibrotic AVS.
authors.affiliation: From the Departments of Internal Medicine (Y.C., D.D.L., H.D., N.D.F., J.C., G.P.H., K.A.Z., M.K.D., R.M.B., M.W.C., R.M.W., D.D.H.), Pharmacology (H.L.K., C.D.S., D.D.H.), Molecular Physiology and Biophysics (M.W.C.), Central Microscopy Research Facility (J.Q.S.), Iowa Institute of Human Genetics Genomics Division (K.L.K.), University of Iowa Carver College of Medicine, Iowa City; Veterans Administration Medical Center, Iowa City (M.W.C.); and Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (D.D.H.).
authors.forename: Yi
authors.initials: Y
authors.lastname: Chu
authors.affiliation: From the Departments of Internal Medicine (Y.C., D.D.L., H.D., N.D.F., J.C., G.P.H., K.A.Z., M.K.D., R.M.B., M.W.C., R.M.W., D.D.H.), Pharmacology (H.L.K., C.D.S., D.D.H.), Molecular Physiology and Biophysics (M.W.C.), Central Microscopy Research Facility (J.Q.S.), Iowa Institute of Human Genetics Genomics Division (K.L.K.), University of Iowa Carver College of Medicine, Iowa City; Veterans Administration Medical Center, Iowa City (M.W.C.); and Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (D.D.H.).
authors.forename: Donald D
authors.initials: DD
authors.lastname: Lund
authors.affiliation: From the Departments of Internal Medicine (Y.C., D.D.L., H.D., N.D.F., J.C., G.P.H., K.A.Z., M.K.D., R.M.B., M.W.C., R.M.W., D.D.H.), Pharmacology (H.L.K., C.D.S., D.D.H.), Molecular Physiology and Biophysics (M.W.C.), Central Microscopy Research Facility (J.Q.S.), Iowa Institute of Human Genetics Genomics Division (K.L.K.), University of Iowa Carver College of Medicine, Iowa City; Veterans Administration Medical Center, Iowa City (M.W.C.); and Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (D.D.H.).
authors.forename: Hardik
authors.initials: H
authors.lastname: Doshi
authors.affiliation: From the Departments of Internal Medicine (Y.C., D.D.L., H.D., N.D.F., J.C., G.P.H., K.A.Z., M.K.D., R.M.B., M.W.C., R.M.W., D.D.H.), Pharmacology (H.L.K., C.D.S., D.D.H.), Molecular Physiology and Biophysics (M.W.C.), Central Microscopy Research Facility (J.Q.S.), Iowa Institute of Human Genetics Genomics Division (K.L.K.), University of Iowa Carver College of Medicine, Iowa City; Veterans Administration Medical Center, Iowa City (M.W.C.); and Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (D.D.H.).
authors.forename: Henry L
authors.initials: HL
authors.lastname: Keen
authors.affiliation: From the Departments of Internal Medicine (Y.C., D.D.L., H.D., N.D.F., J.C., G.P.H., K.A.Z., M.K.D., R.M.B., M.W.C., R.M.W., D.D.H.), Pharmacology (H.L.K., C.D.S., D.D.H.), Molecular Physiology and Biophysics (M.W.C.), Central Microscopy Research Facility (J.Q.S.), Iowa Institute of Human Genetics Genomics Division (K.L.K.), University of Iowa Carver College of Medicine, Iowa City; Veterans Administration Medical Center, Iowa City (M.W.C.); and Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (D.D.H.).
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Knudtson
authors.affiliation: From the Departments of Internal Medicine (Y.C., D.D.L., H.D., N.D.F., J.C., G.P.H., K.A.Z., M.K.D., R.M.B., M.W.C., R.M.W., D.D.H.), Pharmacology (H.L.K., C.D.S., D.D.H.), Molecular Physiology and Biophysics (M.W.C.), Central Microscopy Research Facility (J.Q.S.), Iowa Institute of Human Genetics Genomics Division (K.L.K.), University of Iowa Carver College of Medicine, Iowa City; Veterans Administration Medical Center, Iowa City (M.W.C.); and Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (D.D.H.).
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Funk
authors.affiliation: From the Departments of Internal Medicine (Y.C., D.D.L., H.D., N.D.F., J.C., G.P.H., K.A.Z., M.K.D., R.M.B., M.W.C., R.M.W., D.D.H.), Pharmacology (H.L.K., C.D.S., D.D.H.), Molecular Physiology and Biophysics (M.W.C.), Central Microscopy Research Facility (J.Q.S.), Iowa Institute of Human Genetics Genomics Division (K.L.K.), University of Iowa Carver College of Medicine, Iowa City; Veterans Administration Medical Center, Iowa City (M.W.C.); and Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (D.D.H.).
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Shao
authors.affiliation: From the Departments of Internal Medicine (Y.C., D.D.L., H.D., N.D.F., J.C., G.P.H., K.A.Z., M.K.D., R.M.B., M.W.C., R.M.W., D.D.H.), Pharmacology (H.L.K., C.D.S., D.D.H.), Molecular Physiology and Biophysics (M.W.C.), Central Microscopy Research Facility (J.Q.S.), Iowa Institute of Human Genetics Genomics Division (K.L.K.), University of Iowa Carver College of Medicine, Iowa City; Veterans Administration Medical Center, Iowa City (M.W.C.); and Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (D.D.H.).
authors.forename: Justine
authors.initials: J
authors.lastname: Cheng
authors.affiliation: From the Departments of Internal Medicine (Y.C., D.D.L., H.D., N.D.F., J.C., G.P.H., K.A.Z., M.K.D., R.M.B., M.W.C., R.M.W., D.D.H.), Pharmacology (H.L.K., C.D.S., D.D.H.), Molecular Physiology and Biophysics (M.W.C.), Central Microscopy Research Facility (J.Q.S.), Iowa Institute of Human Genetics Genomics Division (K.L.K.), University of Iowa Carver College of Medicine, Iowa City; Veterans Administration Medical Center, Iowa City (M.W.C.); and Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (D.D.H.).
authors.forename: Georges P
authors.initials: GP
authors.lastname: Hajj
authors.affiliation: From the Departments of Internal Medicine (Y.C., D.D.L., H.D., N.D.F., J.C., G.P.H., K.A.Z., M.K.D., R.M.B., M.W.C., R.M.W., D.D.H.), Pharmacology (H.L.K., C.D.S., D.D.H.), Molecular Physiology and Biophysics (M.W.C.), Central Microscopy Research Facility (J.Q.S.), Iowa Institute of Human Genetics Genomics Division (K.L.K.), University of Iowa Carver College of Medicine, Iowa City; Veterans Administration Medical Center, Iowa City (M.W.C.); and Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (D.D.H.).
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Zimmerman
authors.affiliation: From the Departments of Internal Medicine (Y.C., D.D.L., H.D., N.D.F., J.C., G.P.H., K.A.Z., M.K.D., R.M.B., M.W.C., R.M.W., D.D.H.), Pharmacology (H.L.K., C.D.S., D.D.H.), Molecular Physiology and Biophysics (M.W.C.), Central Microscopy Research Facility (J.Q.S.), Iowa Institute of Human Genetics Genomics Division (K.L.K.), University of Iowa Carver College of Medicine, Iowa City; Veterans Administration Medical Center, Iowa City (M.W.C.); and Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (D.D.H.).
authors.forename: Melissa K
authors.initials: MK
authors.lastname: Davis
authors.affiliation: From the Departments of Internal Medicine (Y.C., D.D.L., H.D., N.D.F., J.C., G.P.H., K.A.Z., M.K.D., R.M.B., M.W.C., R.M.W., D.D.H.), Pharmacology (H.L.K., C.D.S., D.D.H.), Molecular Physiology and Biophysics (M.W.C.), Central Microscopy Research Facility (J.Q.S.), Iowa Institute of Human Genetics Genomics Division (K.L.K.), University of Iowa Carver College of Medicine, Iowa City; Veterans Administration Medical Center, Iowa City (M.W.C.); and Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (D.D.H.).
authors.forename: Robert M
authors.initials: RM
authors.lastname: Brooks
authors.affiliation: From the Departments of Internal Medicine (Y.C., D.D.L., H.D., N.D.F., J.C., G.P.H., K.A.Z., M.K.D., R.M.B., M.W.C., R.M.W., D.D.H.), Pharmacology (H.L.K., C.D.S., D.D.H.), Molecular Physiology and Biophysics (M.W.C.), Central Microscopy Research Facility (J.Q.S.), Iowa Institute of Human Genetics Genomics Division (K.L.K.), University of Iowa Carver College of Medicine, Iowa City; Veterans Administration Medical Center, Iowa City (M.W.C.); and Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (D.D.H.).
authors.forename: Mark W
authors.initials: MW
authors.lastname: Chapleau
authors.affiliation: From the Departments of Internal Medicine (Y.C., D.D.L., H.D., N.D.F., J.C., G.P.H., K.A.Z., M.K.D., R.M.B., M.W.C., R.M.W., D.D.H.), Pharmacology (H.L.K., C.D.S., D.D.H.), Molecular Physiology and Biophysics (M.W.C.), Central Microscopy Research Facility (J.Q.S.), Iowa Institute of Human Genetics Genomics Division (K.L.K.), University of Iowa Carver College of Medicine, Iowa City; Veterans Administration Medical Center, Iowa City (M.W.C.); and Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (D.D.H.).
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
authors.affiliation: From the Departments of Internal Medicine (Y.C., D.D.L., H.D., N.D.F., J.C., G.P.H., K.A.Z., M.K.D., R.M.B., M.W.C., R.M.W., D.D.H.), Pharmacology (H.L.K., C.D.S., D.D.H.), Molecular Physiology and Biophysics (M.W.C.), Central Microscopy Research Facility (J.Q.S.), Iowa Institute of Human Genetics Genomics Division (K.L.K.), University of Iowa Carver College of Medicine, Iowa City; Veterans Administration Medical Center, Iowa City (M.W.C.); and Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (D.D.H.).
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weiss
authors.affiliation: From the Departments of Internal Medicine (Y.C., D.D.L., H.D., N.D.F., J.C., G.P.H., K.A.Z., M.K.D., R.M.B., M.W.C., R.M.W., D.D.H.), Pharmacology (H.L.K., C.D.S., D.D.H.), Molecular Physiology and Biophysics (M.W.C.), Central Microscopy Research Facility (J.Q.S.), Iowa Institute of Human Genetics Genomics Division (K.L.K.), University of Iowa Carver College of Medicine, Iowa City; Veterans Administration Medical Center, Iowa City (M.W.C.); and Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder (D.D.H.). donald-heistad@uiowa.edu.
authors.forename: Donald D
authors.initials: DD
authors.lastname: Heistad
mesh_terms: D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001021:Aortic Valve / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D001024:Aortic Valve Stenosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation; D006937:Hypercholesterolemia / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D006973:Hypertension / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D012083:Renin / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index
chemical_list: C534931:AGT protein, human; D001057:Apolipoproteins E; D017395:Plasminogen Activator Inhibitor 1; D000808:Angiotensinogen; D012083:Renin
keywords: aortic valves; constriction, pathologic; hypercholesterolemia; hypertension; plasminogen activator inhibitor 1