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This Article Full Text Full Text (PDF) All Versions of this Article: 293/2/H949    most recent 01341.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Jagatheesan, G. Articles by Wieczorek, D. F. Search for Related Content PubMed PubMed Citation Articles by Jagatheesan, G. Articles by Wieczorek, D. F.

Rescue of tropomyosin-induced familial hypertrophic cardiomyopathy mice by transgenesis

¹Department of Molecular Genetics, Biochemistry, and Microbiology, ²Institute of Molecular Pharmacology and Biophysics, Department of Surgery, and ³Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; ⁴Department of Physiology and Biophysics, University of Illinois, Chicago College of Medicine, Chicago, Illinois; and ⁵Department of Medicine, University of Maryland, Baltimore, Maryland

Submitted 8 December 2006 ; accepted in final form 4 April 2007

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 -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 -/-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.

hypertrophy; contractile function; genetically altered mice; calcium sensitivity