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Humboldt-Universität zu Berlin - Mathematisch-Naturwissen­schaft­liche Fakultät - Kardiovaskuläre Physik

Humboldt-Universität zu Berlin | Mathematisch-Naturwissen­schaft­liche Fakultät | Institut für Physik | Kardiovaskuläre Physik | Veröffentlichungen | alpha-Tropomyosin mutations Asp(175)Asn and Glu(180)Gly affect cardiac function in transgenic rats in different ways

D. Wernicke, C. Thiel, C. M Duja-Isac, K. V Essin, M. Spindler, D. J Nunez, R. Plehm, N. Wessel, A. Hammes, R. J Edwards, A. Lippoldt, U. Zacharias, H. Stromer, S. Neubauer, M. J Davies, I. Morano, and L. Thierfelder (2004)

alpha-Tropomyosin mutations Asp(175)Asn and Glu(180)Gly affect cardiac function in transgenic rats in different ways

Am. J. Physiol. Regul. Integr. Comp. Physiol., 287:R685–695.

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.

[DOI:http://dx.doi.org/10.1152/ajpregu.00620.200310.1152/ajpregu.00620.2003] [PubMed:http://www.ncbi.nlm.nih.gov/pubmed/1503113815031138]