DOI: 10.1152/ajpheart.2001.280.1.h151. Progression from hypertrophic to dilated cardiomyopathy in mice that express a mutant myosin transgene

Progression from hypertrophic to dilated cardiomyopathy in mice that express a mutant myosin transgene

10.1152/ajpheart.2001.280.1.h151

Crossref journal-article

American Physiological Society

American Journal of Physiology-Heart and Circulatory Physiology (24)

Abstract

A mouse model of hypertrophic cardiomyopathy (HCM) was created by expression of a cardiac α-myosin transgene including the R403Q mutation and a deletion of a segment of the actin-binding domain. HCM mice show early histopathology and hypertrophy, with progressive hypertrophy in females and ventricular dilation in older males. To test the hypothesis that dilated cardiomyopathy (DCM) is part of the pathological spectrum of HCM, we studied chamber morphology, exercise tolerance, hemodynamics, isolated heart function, adrenergic sensitivity, and embryonic gene expression in 8- to 11-mo-old male transgenic animals. Significantly impaired exercise tolerance and both systolic and diastolic dysfunction were seen in vivo. Contraction and relaxation parameters of isolated hearts were also decreased, and lusitropic responsiveness to the β-adrenergic agonist isoproterenol was modestly reduced. Myocardial levels of the G protein-coupled β-adrenergic receptor kinase 1 (β-ARK1) were increased by more than twofold over controls, and total β-ARK1 activity was also significantly elevated. Induction of fetal gene expression was also observed in transgenic hearts. We conclude that transgenic male animals have undergone cardiac decompensation resulting in a DCM phenotype. This supports the idea that HCM and DCM may be part of a pathological continuum rather than independent diseases.

Bibliography

Freeman, K., Colon-Rivera, C., Olsson, M. C., Moore, R. L., Weinberger, H. D., Grupp, I. L., Vikstrom, K. L., Iaccarino, G., Koch, W. J., & Leinwand, L. A. (2001). Progression from hypertrophic to dilated cardiomyopathy in mice that express a mutant myosin transgene. American Journal of Physiology-Heart and Circulatory Physiology, 280(1), H151âH159.

Authors 10

Kalev Freeman (first)
Cynthia Colon-Rivera (additional)
M. Charlotte Olsson (additional)
Russell L. Moore (additional)
Howard D. Weinberger (additional)
Ingrid L. Grupp (additional)
Karen L. Vikstrom (additional)
Guido Iaccarino (additional)
Walter J. Koch (additional)
Leslie A. Leinwand (additional)

References 44 Referenced 50

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Dates

Type	When
Created	7 years, 8 months ago (Dec. 22, 2017, 4:08 a.m.)
Deposited	3 years ago (Aug. 10, 2022, 9:49 p.m.)
Indexed	4 months, 4 weeks ago (April 7, 2025, 2:07 p.m.)
Issued	24 years, 8 months ago (Jan. 1, 2001)
Published	24 years, 8 months ago (Jan. 1, 2001)
Published Print	24 years, 8 months ago (Jan. 1, 2001)

Funders 0

None

BibTeX

@article{Freeman_2001, title={Progression from hypertrophic to dilated cardiomyopathy in mice that express a mutant myosin transgene}, volume={280}, ISSN={1522-1539}, url={http://dx.doi.org/10.1152/ajpheart.2001.280.1.h151}, DOI={10.1152/ajpheart.2001.280.1.h151}, number={1}, journal={American Journal of Physiology-Heart and Circulatory Physiology}, publisher={American Physiological Society}, author={Freeman, Kalev and Colon-Rivera, Cynthia and Olsson, M. Charlotte and Moore, Russell L. and Weinberger, Howard D. and Grupp, Ingrid L. and Vikstrom, Karen L. and Iaccarino, Guido and Koch, Walter J. and Leinwand, Leslie A.}, year={2001}, month=jan, pages={H151–H159} }

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  "abstract": "<jats:p>A mouse model of hypertrophic cardiomyopathy (HCM) was created by expression of a cardiac \u03b1-myosin transgene including the R<jats:sup>403</jats:sup>Q mutation and a deletion of a segment of the actin-binding domain. HCM mice show early histopathology and hypertrophy, with progressive hypertrophy in females and ventricular dilation in older males. To test the hypothesis that dilated cardiomyopathy (DCM) is part of the pathological spectrum of HCM, we studied chamber morphology, exercise tolerance, hemodynamics, isolated heart function, adrenergic sensitivity, and embryonic gene expression in 8- to 11-mo-old male transgenic animals. Significantly impaired exercise tolerance and both systolic and diastolic dysfunction were seen in vivo. Contraction and relaxation parameters of isolated hearts were also decreased, and lusitropic responsiveness to the \u03b2-adrenergic agonist isoproterenol was modestly reduced. Myocardial levels of the G protein-coupled \u03b2-adrenergic receptor kinase 1 (\u03b2-ARK1) were increased by more than twofold over controls, and total \u03b2-ARK1 activity was also significantly elevated. Induction of fetal gene expression was also observed in transgenic hearts. We conclude that transgenic male animals have undergone cardiac decompensation resulting in a DCM phenotype. This supports the idea that HCM and DCM may be part of a pathological continuum rather than independent diseases.</jats:p>",
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