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

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, 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.

• Authors: Dirk Wernicke, Corinna Thiel, Corina M Duja-Isac, Kirill V Essin, Matthias Spindler, Derek J R Nunez, Ralph Plehm, Niels Wessel, Annette Hammes, Robert-J Edwards, Andrea Lippoldt, Ute Zacharias, Hinrik Strömer, Stefan Neubauer, Michael J Davies, Ingo Morano, Ludwig Thierfelder
• Journal: American journal of physiology. Regulatory, integrative and comparative physiology (Am J Physiol Regul Integr Comp Physiol) Vol. 287 Issue 3 Pg. R685-95 (Sep 2004) ISSN: 0363-6119 [Print] United States
• PMID: 15031138 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Tropomyosin
• Aspartic Acid
• Glutamic Acid
• Asparagine
• Calcium
• Glycine

Topics

• Animals
• Animals, Genetically Modified
• Asparagine
• Aspartic Acid
• Biomarkers (analysis)
• Calcium (metabolism, pharmacology)
• Cardiomyopathy, Hypertrophic, Familial (genetics, metabolism, physiopathology)
• Gene Expression
• Glutamic Acid
• Glycine
• Heart (physiopathology)
• Heart Ventricles
• Humans
• Immunohistochemistry
• In Vitro Techniques
• Muscle Fibers, Skeletal (drug effects)
• Mutation, Missense
• Myocardial Contraction
• Myocytes, Cardiac (metabolism)
• Rats
• Sarcomeres (metabolism)
• Transgenes
• Tropomyosin (genetics, metabolism)