AJP - Regu Information on EB 2010
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
QUICK SEARCH:   [advanced]


     

Am J Physiol Regul Integr Comp Physiol (March 18, 2004). doi:10.1152/ajpregu.00620.2003
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
287/3/R685    most recent
00620.2003v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wernicke, D.
Right arrow Articles by Thierfelder, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wernicke, D.
Right arrow Articles by Thierfelder, L.
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.




This article has been cited by other articles:


Home page
 Physiol. Rev.Home page
J. Davis, M. V. Westfall, D. Townsend, M. Blankinship, T. J. Herron, G. Guerrero-Serna, W. Wang, E. Devaney, and J. M. Metzger
Designing Heart Performance by Gene Transfer
Physiol Rev, October 1, 2008; 88(4): 1567 - 1651.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. Rev.Home page
P. Gunning, G. O'neill, and E. Hardeman
Tropomyosin-Based Regulation of the Actin Cytoskeleton in Time and Space
Physiol Rev, January 1, 2008; 88(1): 1 - 35.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
J. Ochala, M. Li, H. Tajsharghi, E. Kimber, M. Tulinius, A. Oldfors, and L. Larsson
Effects of a R133W beta-tropomyosin mutation on regulation of muscle contraction in single human muscle fibres
J. Physiol., June 15, 2007; 581(3): 1283 - 1292.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Visit Other APS Journals Online
Copyright © 2004 by the American Physiological Society.