Decreased left ventricular ejection fraction in transgenic mice expressing mutant cardiac troponin T-Q92, responsible for hypertrophic cardiomyopathy

Do-Sun Lim, Leslie Oberst, Meghan McCluggage, Keith Youker, Jeffrey Lacy, Francesco DeMayo, Mark L. Entman, Robert Roberts, Lloyd H. Michael, Ali J. Marian

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The causality of mutant sarcomeric proteins in hypertrophic cardiomyopathy (HCM) is well established. The current emphasis is to elucidate the pathogenesis of HCM in transgenic animal models. We determined the left ventricular ejection fraction (LVEF) in transgenic mice expressing mutant cardiac troponin T (cTnT)-Q92, known to cause HCM in humans. Transgenes were constructed by placing wild-type (R92) or mutant (Q92) full-length human cTnT cDNAs 3' into a 5.5-kb murine [α-myosin heavy chain (MyHC)] promoter injected into fertilized zygotes. Three wild-type and six mutant lines were produced. Transgene mRNA and proteins, detected using transgene-specific probes were expressed at high levels in all wild-type and three mutant lines. The total cTnT mRNA pool was increased by up to five-fold in transgenic mice, but the total cTnT protein remained unchanged. The mean values of LVEF, determined by 178Ta radionuclide angiography, were 5 7.8 ± 6% (n = 4) in non-transgenic littermate (NLM). 53.3 ± 10 (n = 6) in wild-type and 39.4 ± 6 (n = 5) in mutant transgenic mice (P= 0.009). The heart/body weight ratios and the number of cells stained with terminal deoxynucleotidyl transferase (TdT)-mediated nick end-labeling were similar among the groups. Three mutant mice had myocyte disarray and excess interstitial collagen and two had normal myocardial structure despite having reduced LVEF. Thus, in vivo expression of the mutant cTnT-Q92 protein, responsible for human HCM, impaired global cardiac systolic function in transgenic mice, which also occurred in the absence of myocyte disarray and increased interstitial collagen. (C) 2000 Academic Press.

Original languageEnglish
Pages (from-to)365-374
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume32
Issue number3
DOIs
Publication statusPublished - 2000 Sep 14
Externally publishedYes

Fingerprint

Troponin T
Hypertrophic Cardiomyopathy
Stroke Volume
Transgenic Mice
Transgenes
Muscle Cells
Collagen
Radionuclide Angiography
Messenger RNA
Genetically Modified Animals
Proteins
DNA Nucleotidylexotransferase
Myosin Heavy Chains
Zygote
Mutant Proteins
Causality
Animal Models
Complementary DNA
Cell Count
Body Weight

Keywords

  • Collagen
  • Ejection fraction
  • Gene expression
  • Hypertrophic cardiomyopathy
  • Mutation
  • Myocyte disarray
  • Radionuclide angiography
  • Transgenic mouse
  • Troponin T

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Decreased left ventricular ejection fraction in transgenic mice expressing mutant cardiac troponin T-Q92, responsible for hypertrophic cardiomyopathy. / Lim, Do-Sun; Oberst, Leslie; McCluggage, Meghan; Youker, Keith; Lacy, Jeffrey; DeMayo, Francesco; Entman, Mark L.; Roberts, Robert; Michael, Lloyd H.; Marian, Ali J.

In: Journal of Molecular and Cellular Cardiology, Vol. 32, No. 3, 14.09.2000, p. 365-374.

Research output: Contribution to journalArticle

Lim, Do-Sun ; Oberst, Leslie ; McCluggage, Meghan ; Youker, Keith ; Lacy, Jeffrey ; DeMayo, Francesco ; Entman, Mark L. ; Roberts, Robert ; Michael, Lloyd H. ; Marian, Ali J. / Decreased left ventricular ejection fraction in transgenic mice expressing mutant cardiac troponin T-Q92, responsible for hypertrophic cardiomyopathy. In: Journal of Molecular and Cellular Cardiology. 2000 ; Vol. 32, No. 3. pp. 365-374.
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AU - Oberst, Leslie

AU - McCluggage, Meghan

AU - Youker, Keith

AU - Lacy, Jeffrey

AU - DeMayo, Francesco

AU - Entman, Mark L.

AU - Roberts, Robert

AU - Michael, Lloyd H.

AU - Marian, Ali J.

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AB - The causality of mutant sarcomeric proteins in hypertrophic cardiomyopathy (HCM) is well established. The current emphasis is to elucidate the pathogenesis of HCM in transgenic animal models. We determined the left ventricular ejection fraction (LVEF) in transgenic mice expressing mutant cardiac troponin T (cTnT)-Q92, known to cause HCM in humans. Transgenes were constructed by placing wild-type (R92) or mutant (Q92) full-length human cTnT cDNAs 3' into a 5.5-kb murine [α-myosin heavy chain (MyHC)] promoter injected into fertilized zygotes. Three wild-type and six mutant lines were produced. Transgene mRNA and proteins, detected using transgene-specific probes were expressed at high levels in all wild-type and three mutant lines. The total cTnT mRNA pool was increased by up to five-fold in transgenic mice, but the total cTnT protein remained unchanged. The mean values of LVEF, determined by 178Ta radionuclide angiography, were 5 7.8 ± 6% (n = 4) in non-transgenic littermate (NLM). 53.3 ± 10 (n = 6) in wild-type and 39.4 ± 6 (n = 5) in mutant transgenic mice (P= 0.009). The heart/body weight ratios and the number of cells stained with terminal deoxynucleotidyl transferase (TdT)-mediated nick end-labeling were similar among the groups. Three mutant mice had myocyte disarray and excess interstitial collagen and two had normal myocardial structure despite having reduced LVEF. Thus, in vivo expression of the mutant cTnT-Q92 protein, responsible for human HCM, impaired global cardiac systolic function in transgenic mice, which also occurred in the absence of myocyte disarray and increased interstitial collagen. (C) 2000 Academic Press.

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