Rescue of tropomyosin-induced familial hypertrophic cardiomyopathy mice by transgenesis

Ganapathy Jagatheesan, Sudarsan Rajan, Natalia Petrashevskaya, Arnold Schwartz, Greg Boivin, Grace M. Arteaga, R. John Solaro, Stephen B. Liggett, David F. Wieczorek

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42 Scopus citations

Abstract

Familial hypertrophic cardiomyopathy (FHC) is a disease caused by mutations in contractile proteins of the sarcomere. Our laboratory developed a mouse model of FHC with a mutation in the thin filament protein α-tropomyosin (TM) at amino acid 180 (Glu180Gly). The hearts of these mice exhibit dramatic systolic and diastolic dysfunction, and their myofilaments demonstrate increased calcium sensitivity. The mice also develop severe cardiac hypertrophy, with death ensuing by 6 mo. In an attempt to normalize calcium sensitivity in the cardiomyofilaments of the hypertrophic mice, we generated a chimeric α-/β-TM protein that decreases calcium sensitivity in transgenic mouse cardiac myofilaments. By mating mice from these two models together, we tested the hypothesis that an attenuation of myofilament calcium sensitivity would modulate the severe physiological and pathological consequences of the FHC mutation. These double-transgenic mice "rescue" the hypertrophic phenotype by exhibiting a normal morphology with no pathological abnormalities. Physiological analyses of these rescued mice show improved cardiac function and normal myofilament calcium sensitivity. These results demonstrate that alterations in calcium response by modification of contractile proteins can prevent the pathological and physiological effects of this disease.

Original languageEnglish (US)
Pages (from-to)H949-H958
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume293
Issue number2
DOIs
StatePublished - Aug 1 2007

Keywords

  • Calcium sensitivity
  • Contractile function
  • Genetically altered mice
  • Hypertrophy

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Jagatheesan, G., Rajan, S., Petrashevskaya, N., Schwartz, A., Boivin, G., Arteaga, G. M., Solaro, R. J., Liggett, S. B., & Wieczorek, D. F. (2007). Rescue of tropomyosin-induced familial hypertrophic cardiomyopathy mice by transgenesis. American Journal of Physiology - Heart and Circulatory Physiology, 293(2), H949-H958. https://doi.org/10.1152/ajpheart.01341.2006