Fibrotic Aortic Valve Stenosis in Hypercholesterolemic/Hypertensive Mice

Yi Chu; Donald D Lund; Hardik Doshi; Henry L Keen; Kevin L Knudtson; Nathan D Funk; Jian Q Shao; Justine Cheng; Georges P Hajj; Kathy A Zimmerman; Melissa K Davis; Robert M Brooks; Mark W Chapleau; Curt D Sigmund; Robert M Weiss; Donald D Heistad

doi:10.1161/ATVBAHA.115.306912

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Fibrotic Aortic Valve Stenosis in Hypercholesterolemic/Hypertensive Mice

Journal article

Open access

Peer reviewed

Fibrotic Aortic Valve Stenosis in Hypercholesterolemic/Hypertensive Mice

Yi Chu, Donald D Lund, Hardik Doshi, Henry L Keen, Kevin L Knudtson, Nathan D Funk, Jian Q Shao, Justine Cheng, Georges P Hajj, Kathy A Zimmerman, …

Arteriosclerosis, thrombosis, and vascular biology, Vol.36(3), pp.466-474

03/2016

DOI: 10.1161/ATVBAHA.115.306912

PMCID: PMC4767592

PMID: 26769049

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Abstract

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. 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. 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.

Renin - metabolism

Apolipoproteins E - deficiency

Male

Aortic Valve - pathology

Renin - genetics

Plasminogen Activator Inhibitor 1 - metabolism

Aortic Valve Stenosis - etiology

Female

Hypertension - genetics

Plasminogen Activator Inhibitor 1 - genetics

Disease Models, Animal

Severity of Illness Index

Mice, Inbred C57BL

Aortic Valve Stenosis - physiopathology

Gene Expression Regulation

Aortic Valve - physiopathology

Angiotensinogen - metabolism

Aortic Valve - metabolism

Hypertension - metabolism

Mice, Knockout

Angiotensinogen - genetics

Animals

Aortic Valve Stenosis - pathology

Apolipoproteins E - genetics

Fibrosis

Hypertension - complications

Aortic Valve Stenosis - metabolism

Hypercholesterolemia - complications

Hypercholesterolemia - genetics

Hypercholesterolemia - metabolism

Details

Title: Subtitle: Fibrotic Aortic Valve Stenosis in Hypercholesterolemic/Hypertensive Mice
Creators: Yi Chu - 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 D Lund - 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.)
Hardik Doshi - 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.)
Henry L Keen - 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.)
Kevin L Knudtson - 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.)
Nathan D Funk - 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.)
Jian Q Shao - 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.)
Justine Cheng - 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.)
Georges P Hajj - 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.)
Kathy A Zimmerman - 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.)
Melissa K Davis - 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.)
Robert M Brooks - 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.)
Mark W Chapleau - 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.)
Curt D Sigmund - 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.)
Robert M Weiss - 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 D Heistad - 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
Resource Type: Journal article
Publication Details: Arteriosclerosis, thrombosis, and vascular biology, Vol.36(3), pp.466-474
Publisher: United States
DOI: 10.1161/ATVBAHA.115.306912
PMID: 26769049
PMCID: PMC4767592
ISSN: 1079-5642
eISSN: 1524-4636
Grant note: R01 HL125603 / NHLBI NIH HHS S10 OD019941 / NIH HHS HL62984 / NHLBI NIH HHS P01 HL014388 / NHLBI NIH HHS P01 HL062984 / NHLBI NIH HHS HL14388 / NHLBI NIH HHS OD019941 / NIH HHS
Language: English
Date published: 03/2016
Academic Unit: Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine; Iowa Institute of Human Genetics
Record Identifier: 9984025458402771

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