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α-Tropomyosin mutations Asp175Asn and Glu180Gly affect cardiac function in transgenic rats in different ways

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 (+5 others)
2004 American Journal of Physiology. Regulatory Integrative and Comparative Physiology  

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ajpregu.00620.2003.-To study the mechanisms by which missense mutations in ␣-tropomyosin cause familial hypertrophic cardiomyopathy, we generated transgenic rats overexpressing ␣-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 humanspecific anti-␣-tropomyosin antibody,
more » ... ARG1. In transgenic rats with either ␣-tropomyosin mutation, molecular markers of cardiac hypertrophy were induced. Ca 2ϩ 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 2ϩ waves were detected only in cardiomyocytes from animals with mutation Asp 175 Asn, suggesting an increase in intracellular Ca 2ϩ concentration compensating for the reduced Ca 2ϩ sensitivity of isometric force generation. Accordingly, in Langendorffperfused 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 ␣-tropomyosin mutation Asp 175 Asn in familial hypertrophic cardiomyopathy on the basis of changes in Ca 2ϩ handling as a sensitive mechanism to compensate for alterations in sarcomeric structure. familial hypertrophic cardiomyopathy; animal model; calcium transient; cardiac skinned-fiber preparation
doi:10.1152/ajpregu.00620.2003 pmid:15031138 fatcat:mklsflpa6nawfajfkvpdgh5vpm
Citation

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. "α-Tropomyosin mutations Asp175Asn and Glu180Gly affect cardiac function in transgenic rats in different ways." American Journal of Physiology. Regulatory Integrative and Comparative Physiology (2004) R685-R695