Cited by 181Cardiomyopathy and Myosin StudiesCardiac Fibrosis and RemodelingCardiac electrophysiology and arrhythmias

A transgenic rabbit model for human hypertrophic cardiomyopathy

Open access
Marian, Ali J., Wu, Yun, Lim, Do-Sun, McCluggage, Meghan, Youker, Keith, Yu, Qun-tao, Brugada, Ramon, DeMayo, Francesco +2 more·1999·Journal of Clinical Investigation

Abstract

Certain mutations in genes for sarcomeric proteins cause hypertrophic cardiomyopathy (HCM). We have developed a transgenic rabbit model for HCM caused by a common point mutation in the beta-myosin heavy chain (MyHC) gene, R400Q. Wild-type and mutant human beta-MyHC cDNAs were cloned 3' to a 7-kb murine beta-MyHC promoter. We injected purified transgenes into fertilized zygotes to generate two lines each of the wild-type and mutant transgenic rabbits. Expression of transgene mRNA and protein were confirmed by Northern blotting and 2-dimensional gel electrophoresis followed by immunoblotting, respectively. Animals carrying the mutant transgene showed substantial myocyte disarray and a 3-fold increase in interstitial collagen expression in their myocardia. Mean septal thicknesses were comparable between rabbits carrying the wild type transgene and their nontransgenic littermates (NLMs) but were significantly increased in the mutant transgenic animals. Posterior wall thickness and left ventricular mass were also increased, but dimensions and systolic function were normal. Premature death was more common in mutant than in wild-type transgenic rabbits or in NLMs. Thus, cardiac expression of beta-MyHC-Q(403) in transgenic rabbits induced hypertrophy, myocyte and myofibrillar disarray, interstitial fibrosis, and premature death, phenotypes observed in humans patients with HCM due to beta-MyHC-Q(403).

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  • Rabbits harboring human hypertrophic cardiomyopathy mutations often better recapitulate this category of human diseases than their murine model equivalents.

    “rabbits harboring human hypertrophic cardiomyopathy mutations often better recapitulate this category of human diseases than their murine model equivalents (Marian, et al., 1999; Sanbe, et al., 2005).”

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Research works printed but not linked: 2

  1. Marian, A.J., and Roberts, R. 2000. Molecular pathogenesis of car- diomyopathies. In Cardiovascular pathology and physiology. 4th ed. N. Spere- lakis, editor. Academic Press. San Diego, CA. In press.
  2. Lim D-S, et al. Decreased left ventricular ejection fraction, detected by 178 Ta radionuclide angiography, in transgenic mice expressing a mutant cardiac troponin T-Gln 92 : altered function precedes structural abnor- malities. J. Mol. Cell. Cardiol. In press.

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Authors
Marian, A. J., Wu, Y., Lim, D.-S., McCluggage, M., Youker, K., Yu, Q.-T., Brugada, R., DeMayo, F., Quinones, M., & Roberts, R.
Affiliations
Baylor College of Medicine (US)
Venue
Journal of Clinical Investigation
Published
1999-12-15
Volume
104
Issue
12
Pages
1683-1692
ISSN
0021-9738 (ISSN-L)
OpenAlex
W2123240976
Cited by
181
References
62
Citations by year
2025: 3 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 6 · 2020: 5 · 2019: 7 · 2018: 2 · 2017: 4 · 2016: 8 · 2015: 2 · 2014: 6 · 2013: 5 · 2012: 6
FWCI
9.24
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Heart Association
  • National Institutes of Health (5p50hl042267-04)
  • National Heart, Lung, and Blood Institute (P50-HL-42267-01)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
Keywords
hypertrophic cardiomyopathy, beta-myosin heavy chain, transgenic rabbit model, sarcomeric protein mutations, myocyte disarray, interstitial fibrosis, left ventricular hypertrophy, premature mortality
MeSH terms
Animals, Cardiomyopathy, Hypertrophic, Collagen, Disease Models, Animal, Humans, Rabbits, RNA, Messenger, Myosin Heavy Chains, Animals, Genetically Modified

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