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Am J Physiol Regul Integr Comp Physiol (March 18, 2004). doi:10.1152/ajpregu.00620.2003
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Submitted on October 24, 2003
Accepted on March 8, 2004

{alpha}-tropomyosin mutations Asp175Asn and Glu180Gly affect cardiac function in transgenic rats in different ways

Dirk Wernicke1*, Corinna Thiel1, Corina M Duja-Isac1, Kirill V Essine1, Matthias Spindler2, Derek J. R Nunez3, Ralph Plehm1, Niels Wessel4, Annette Hammes1, Robert-J. Edwards3, Andrea Lippoldt1, Ute Zacharias1, Hinrik Stroemer2, Stefan Neubauer2, Michael J Davies5, Ingo Morano1, and Ludwig Thierfelder1

1 Department of Cardiology, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
2 Department of Cardiology, Clinic of Internal Medicine, Julius-Maximilians-University, Wuerzburg, Germany
3 Section on Clinical Pharmacology, Imperial College School of Medicine, Hammersmith Hospital, London, London, United Kingdom
4 Franz Volhard Clinic, Charite of the Humboldt University, Berlin, Germany
5 St. George's Hospital Medical School, London, United Kingdom

* To whom correspondence should be addressed. E-mail: dwernic{at}mdc-berlin.de.

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 the molecular, morphological, and physiological level. 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 was decreased, but not with mutation Glu180Gly. 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 Ca2+ 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 based on changes in Ca2+ handling as a sensitive mechanism to compensate for alterations in the sarcomeric structure.




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