title: 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.affiliation: Max-Delbrück Center for Molecular Medicine, Robert-Roessle-Str. 10, Berlin 13092, Germany. dwernic@mdc-berlin.de
authors.forename: Dirk
authors.initials: D
authors.lastname: Wernicke
authors.forename: Corinna
authors.initials: C
authors.lastname: Thiel
authors.forename: Corina M
authors.initials: CM
authors.lastname: Duja-Isac
authors.forename: Kirill V
authors.initials: KV
authors.lastname: Essin
authors.forename: Matthias
authors.initials: M
authors.lastname: Spindler
authors.forename: Derek J R
authors.initials: DJ
authors.lastname: Nunez
authors.forename: Ralph
authors.initials: R
authors.lastname: Plehm
authors.forename: Niels
authors.initials: N
authors.lastname: Wessel
authors.forename: Annette
authors.initials: A
authors.lastname: Hammes
authors.forename: Robert-J
authors.initials: RJ
authors.lastname: Edwards
authors.forename: Andrea
authors.initials: A
authors.lastname: Lippoldt
authors.forename: Ute
authors.initials: U
authors.lastname: Zacharias
authors.forename: Hinrik
authors.initials: H
authors.lastname: Strömer
authors.forename: Stefan
authors.initials: S
authors.lastname: Neubauer
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Davies
authors.forename: Ingo
authors.initials: I
authors.lastname: Morano
authors.forename: Ludwig
authors.initials: L
authors.lastname: Thierfelder
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001216:Asparagine; D001224:Aspartic Acid; D015415:Biomarkers / Q000032:analysis; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D015870:Gene Expression; D018698:Glutamic Acid; D005998:Glycine; D006321:Heart / Q000503:physiopathology*; D006352:Heart Ventricles; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D018485:Muscle Fibers, Skeletal / Q000187:drug effects; D020125:Mutation, Missense; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D012518:Sarcomeres / Q000378:metabolism; D019076:Transgenes; D014335:Tropomyosin / Q000235:genetics* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D014335:Tropomyosin; D001224:Aspartic Acid; D018698:Glutamic Acid; D001216:Asparagine; D002118:Calcium; D005998:Glycine