A transgenic rabbit model for human hypertrophic cardiomyopathy

Ali J. Marian, Yun Wu, Do Sun Lim, Meghan McCluggage, Keith A. Youker, Qun Tao Yu, Ramon Brugada, Francesco DeMayo, Miguel A. Quiñones, Robert Roberts

Research output: Contribution to journalArticlepeer-review

155 Scopus citations

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 β-myosin heavy chain (MyHC) gene, R400Q. Wild-type and mutant human β-MyHC cDNAs were cloned 3' to a 7-kb murine β-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 β-MyHC-Q403 in transgenic rabbits induced hypertrophy, myocyte and myofibrillar disarray, interstitial fibrosis, and premature death, phenotypes observed in humans patients with HCM due to β-MyHC-Q403.

Original languageEnglish (US)
Pages (from-to)1683-1692
Number of pages10
JournalJournal of Clinical Investigation
Volume104
Issue number12
DOIs
StatePublished - Dec 1999

ASJC Scopus subject areas

  • General Medicine

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