Spontaneous Aortic Regurgitation and Valvular Cardiomyopathy in Mice

Georges P Hajj; Yi Chu; Donald D Lund; Jason A Magida; Nathan D Funk; Robert M Brooks; Gary L Baumbach; Kathy A Zimmerman; Melissa K Davis; Ramzi N El Accaoui; Tariq Hameed; Hardik Doshi; BiYi Chen; Leslie A Leinwand; Long-Sheng Song; Donald D Heistad; Robert M Weiss

doi:10.1161/ATVBAHA.115.305729

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Spontaneous Aortic Regurgitation and Valvular Cardiomyopathy in Mice

Journal article

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Peer reviewed

Spontaneous Aortic Regurgitation and Valvular Cardiomyopathy in Mice

Georges P Hajj, Yi Chu, Donald D Lund, Jason A Magida, Nathan D Funk, Robert M Brooks, Gary L Baumbach, Kathy A Zimmerman, Melissa K Davis, Ramzi N El Accaoui, …

Arteriosclerosis, thrombosis, and vascular biology, Vol.35(7), pp.1653-1662

07/2015

DOI: 10.1161/ATVBAHA.115.305729

PMCID: PMC4482792

PMID: 25997932

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Abstract

We studied the mechanistic links between fibrocalcific changes in the aortic valve and aortic valve function in mice homozygous for a hypomorphic epidermal growth factor receptor mutation (Wave mice). We also studied myocardial responses to aortic valve dysfunction in Wave mice. At 1.5 months of age, before development of valve fibrosis and calcification, aortic regurgitation, but not aortic stenosis, was common in Wave mice. Aortic valve fibrosis, profibrotic signaling, calcification, osteogenic markers, lipid deposition, and apoptosis increased dramatically by 6 and 12 months of age in Wave mice. Aortic regurgitation remained prevalent, however, and aortic stenosis was rare, at all ages. Proteoglycan content was abnormally increased in aortic valves of Wave mice at all ages. Treatment with pioglitazone prevented abnormal valve calcification, but did not protect valve function. There was significant left ventricular volume overload, hypertrophy, and fetal gene expression, at all ages in Wave mice with aortic regurgitation. Left ventricular systolic function was normal until 6 months of age in Wave mice, but became impaired by 12 months of age. Myocardial transverse tubules were normal in the presence of left ventricular hypertrophy at 1.5 and 3 months of age, but became disrupted by 12 months of age. We present the first comprehensive phenotypic and molecular characterization of spontaneous aortic regurgitation and volume-overload cardiomyopathy in an experimental model. In Wave mice, fibrocalcific changes are not linked to valve dysfunction and are epiphenomena arising from structurally incompetent myxomatous valves.

Heart Valve Diseases - pathology

Actins - metabolism

Aortic Valve - drug effects

Systole

Aortic Valve - pathology

Mice, Mutant Strains

Cell Death

Thiazolidinediones - pharmacology

Heart Valve Diseases - physiopathology

Gene Expression

Osteocalcin - metabolism

Aortic Valve - physiopathology

Aortic Valve Insufficiency - physiopathology

Proteoglycans - metabolism

Aortic Valve Insufficiency - pathology

Lipid Metabolism

Disease Progression

Transcription Factors - metabolism

Animals

Fibrosis

Sp7 Transcription Factor

Calcinosis - prevention & control

Mice

Calcinosis - pathology

Transforming Growth Factor beta - metabolism

Details

Title: Subtitle: Spontaneous Aortic Regurgitation and Valvular Cardiomyopathy in Mice
Creators: Georges P Hajj - From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder
Yi Chu - From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder
Donald D Lund - From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder
Jason A Magida - From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder
Nathan D Funk - From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder
Robert M Brooks - From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder
Gary L Baumbach - From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder
Kathy A Zimmerman - From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder
Melissa K Davis - From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder
Ramzi N El Accaoui - From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder
Tariq Hameed - From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder
Hardik Doshi - From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder
BiYi Chen - From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder
Leslie A Leinwand - From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder
Long-Sheng Song - From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder
Donald D Heistad - From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder. robert-weiss@uiowa.edu donald-heistad@uiowa.edu
Robert M Weiss - From the Department of Internal Medicine (G.P.H., Y.C., D.D.L., N.D.F., R.M.B., K.A.Z., M.K.D., R.N.E.A., T.H., H.D., B.C., L.-S.S., D.D.H., R.M.W.), Department of Pharmacology (D.D.H.), and Department of Pathology (G.L.B.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City; and Department of Molecular, Cellular, and Developmental Biology (J.A.M., L.A.L., D.D.H.), University of Colorado, Boulder. robert-weiss@uiowa.edu donald-heistad@uiowa.edu
Resource Type: Journal article
Publication Details: Arteriosclerosis, thrombosis, and vascular biology, Vol.35(7), pp.1653-1662
Publisher: United States
DOI: 10.1161/ATVBAHA.115.305729
PMID: 25997932
PMCID: PMC4482792
ISSN: 1079-5642
eISSN: 1524-4636
Grant note: S10 OD019941 / NIH HHS HL090905 / NHLBI NIH HHS HL62984 / NHLBI NIH HHS P01 HL062984 / NHLBI NIH HHS S10 RR026293 / NCRR NIH HHS R01 HL090905 / NHLBI NIH HHS ODO019941 / PHS HHS RR 026293 / NCRR NIH HHS
Language: English
Date published: 07/2015
Academic Unit: Radiology; Pathology; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984040339902771

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