A transgenic rabbit model for human hypertrophic cardiomyopathy
Open accessAbstract
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).”
From Small and large animal models in cardiac contraction research: advantages and disadvantages (2014) · cites this paper as Marian, et al., 1999
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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)
- PMC
- PMC409884
- 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
- bronze
- doi.org
- 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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