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To study the mechanisms by which missense mutations in alpha-tropomyosin cause familial hypertrophic cardiomyopathy, we generated transgenic rats overexpressing alpha-tropomyosin with one of two disease-causing mutations, Asp(175)Asn or Glu(180)Gly, and analyzed phenotypic changes at molecular, morphological, and physiological levels. The transgenic proteins were stably integrated into the sarcomere, as shown by immunohistochemistry using a human-specific anti-alpha-tropomyosin antibody, ARG1. In transgenic rats with either alpha-tropomyosin mutation, molecular markers of cardiac hypertrophy were induced. Ca(2+) sensitivity of cardiac skinned-fiber preparations from animals with mutation Asp(175)Asn, but not Glu(180)Gly, was decreased. Furthermore, elevated frequency and amplitude of spontaneous Ca(2+) waves were detected only in cardiomyocytes from animals with mutation Asp(175)Asn, suggesting an increase in intracellular Ca(2+) concentration compensating for the reduced Ca(2+) sensitivity of isometric force generation. Accordingly, in Langendorff-perfused heart preparations, myocardial contraction and relaxation were accelerated in animals with mutation Asp(175)Asn. The results allow us to propose a hypothesis of the pathogenetic changes caused by alpha-tropomyosin mutation Asp(175)Asn in familial hypertrophic cardiomyopathy on the basis of changes in Ca(2+) handling as a sensitive mechanism to compensate for alterations in sarcomeric structure.

Original publication

DOI

10.1152/ajpregu.00620.2003

Type

Journal article

Journal

Am J Physiol Regul Integr Comp Physiol

Publication Date

09/2004

Volume

287

Pages

R685 - R695

Keywords

Animals, Animals, Genetically Modified, Asparagine, Aspartic Acid, Biomarkers, Calcium, Cardiomyopathy, Hypertrophic, Familial, Gene Expression, Glutamic Acid, Glycine, Heart, Heart Ventricles, Humans, Immunohistochemistry, In Vitro Techniques, Muscle Fibers, Skeletal, Mutation, Missense, Myocardial Contraction, Myocytes, Cardiac, Rats, Sarcomeres, Transgenes, Tropomyosin