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

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Item Type:	Article
Title:	α-tropomyosin mutations Asp175Asn and Glu180Gly affect cardiac function in transgenic rats in different ways
Creators Name:	Wernicke, D., Thiel, C., Duja-Isac, C.M., Essine, K.V., Spindler, M., Nunez, D.J.R., Plehm, R., Wessel, N., Hammes, A., Edwards, R.J., Lippoldt, A., Zacharias, U., Stroemer, H., Neubauer, S., Davies, M.J., 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
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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