Abstract |
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.
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Authors | Dirk Wernicke, Corinna Thiel, Corina M Duja-Isac, Kirill V Essin, Matthias Spindler, Derek J R Nunez, Ralph Plehm, Niels Wessel, Annette Hammes, Robert-J Edwards, Andrea Lippoldt, Ute Zacharias, Hinrik Strömer, Stefan Neubauer, Michael J Davies, Ingo Morano, Ludwig Thierfelder |
Journal | American journal of physiology. Regulatory, integrative and comparative physiology
(Am J Physiol Regul Integr Comp Physiol)
Vol. 287
Issue 3
Pg. R685-95
(Sep 2004)
ISSN: 0363-6119 [Print] United States |
PMID | 15031138
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Biomarkers
- Tropomyosin
- Aspartic Acid
- Glutamic Acid
- Asparagine
- Calcium
- Glycine
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Topics |
- Animals
- Animals, Genetically Modified
- Asparagine
- Aspartic Acid
- Biomarkers
(analysis)
- Calcium
(metabolism, pharmacology)
- Cardiomyopathy, Hypertrophic, Familial
(genetics, metabolism, physiopathology)
- Gene Expression
- Glutamic Acid
- Glycine
- Heart
(physiopathology)
- Heart Ventricles
- Humans
- Immunohistochemistry
- In Vitro Techniques
- Muscle Fibers, Skeletal
(drug effects)
- Mutation, Missense
- Myocardial Contraction
- Myocytes, Cardiac
(metabolism)
- Rats
- Sarcomeres
(metabolism)
- Transgenes
- Tropomyosin
(genetics, metabolism)
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