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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

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

¹Max-Delbrück Center for Molecular Medicine, 13 092 Berlin; ²Clinic of Internal Medicine, Julius-Maximilians University, 97 080 Würzburg; and ⁴Franz Volhard Clinic, Charite of the Humboldt University, 13125 Berlin, Germany; ³Section on Clinical Pharmacology, Imperial College School of Medicine, Hammersmith Hospital, London W12 ONN; and ⁵St. George's Hospital Medical School, London SW17 ORE, United Kingdom

Submitted 24 October 2003 ; accepted in final form 8 March 2004

To study the mechanisms by which missense mutations in -tropomyosin cause familial hypertrophic cardiomyopathy, we generated transgenic rats overexpressing -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--tropomyosin antibody, ARG1. In transgenic rats with either -tropomyosin mutation, molecular markers of cardiac hypertrophy were induced. Ca²⁺ sensitivity of cardiac skinned-fiber preparations from animals with mutation Asp¹⁷⁵Asn, but not Glu¹⁸⁰Gly, 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 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 -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.

familial hypertrophic cardiomyopathy; animal model; calcium transient; cardiac skinned-fiber preparation

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