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

Item Type:Article
Title:α-tropomyosin mutations Asp175Asn and Glu180Gly affect cardiac function in transgenic rats in different ways
Creators Name:Wernicke, D. and Thiel, C. and Duja-Isac, C.M. and Essine, K.V. and Spindler, M. and Nunez, D.J.R. and Plehm, R. and Wessel, N. and Hammes, A. and Edwards, R.J. and Lippoldt, A. and Zacharias, U. and Stroemer, H. and Neubauer, S. and Davies, M.J. and Morano, I. and Thierfelder, L.
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, Asp175Asn or Glu180Gly, 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. Ca2+ sensitivity of cardiac skinned-fiber preparations from animals with mutation Asp175Asn, but not Glu 180Gly, was decreased. Furthermore, elevated frequency and amplitude of spontaneous Ca2+ waves were detected only in cardiomyocytes from animals with mutation Asp175Asn, suggesting an increase in intracellular Ca2+ 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 Asp175Asn. The results allow us to propose a hypothesis of the pathogenetic changes caused by {alpha}-tropomyosin mutation Asp175Asn in familial hypertrophic cardiomyopathy on the basis of changes in Ca2+ handling as a sensitive mechanism to compensate for alterations in sarcomeric structure.
Keywords:Animal Model, Calcium Transient, Cardiac Skinned-Fiber Preparation, Familial Hypertrophic Cardiomyopathy
Source:American Journal of Physiology Regulatory Integrative and Comparative Physiology
ISSN:0363-6119
Publisher:American Physiological Society (U.S.A.)
Volume:287
Number:3
Page Range:R685-R695
Date:1 September 2004
Official Publication:https://doi.org/10.1152/ajpregu.00620.2003
PubMed:View item in PubMed

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