title: Differential interactions of thin filament proteins in two cardiac troponin T mouse models of hypertrophic and dilated cardiomyopathies.
abstract: OBJECTIVE
  Mutations in a sarcomeric protein can cause hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM), the opposite ends of a spectrum of phenotypic responses of the heart to mutations. We posit the contracting phenotypes could result from differential effects of the mutant proteins on interactions among the sarcomeric proteins. To test the hypothesis, we generated transgenic mice expressing either cardiac troponin T (cTnT)-Q92 or cTnT-W141, known to cause HCM and DCM, respectively, in the heart.
  
  
  RESULTS
  We phenotyped the mice by echocardiography, histology and immunoblotting, and real-time polymerase chain reaction. We detected interactions between the sarcomeric proteins by co-immunoprecipitation and determined Ca2+ sensitivity of myofibrillar protein ATPase activity by Carter assay. The cTnT-W141 mice exhibited dilated hearts and decreased systolic function. In contrast, the cTnT-Q92 mice showed smaller ventricles and enhanced systolic function. Levels of cardiac troponin I, cardiac alpha-actin, alpha-tropomyosin, and cardiac troponin C co-immunoprecipitated with anti-cTnT antibodies were higher in the cTnT-W141 than in the cTnT-Q92 mice, as were levels of alpha-tropomyosin co-immunoprecipitated with an anti-cardiac alpha-actin antibody. In contrast, levels of cardiac troponin I co-immunoprecipitated with an anti-cardiac alpha-actin antibody were higher in the cTnT-Q92 mice. Ca2+ sensitivity of myofibrillar ATPase activity was increased in HCM but decreased in DCM mice compared with non-transgenic mice.
  
  
  CONCLUSIONS
  Differential interactions among the sarcomeric proteins containing cTnT-Q92 or cTnT-W141 are responsible for the contrasting phenotypes of HCM or DCM, respectively.
authors: Center for Cardiovascular Genetic Research, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, 6770 Bertner Street, Suite C900A, Houston, TX 77030, USA.
authors: Raffaella
authors: R
authors: Lombardi
authors: Achim
authors: A
authors: Bell
authors: Vinitha
authors: V
authors: Senthil
authors: Jasvinder
authors: J
authors: Sidhu
authors: Michela
authors: M
authors: Noseda
authors: Robert
authors: R
authors: Roberts
authors: Ali J
authors: AJ
authors: Marian
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D009320:Atrial Natriuretic Factor; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D020098:Natriuretic Peptide, C-Type / Q000378:metabolism; D010641:Phenotype; D011498:Protein Precursors / Q000378:metabolism; D012518:Sarcomeres / Q000378:metabolism; D020107:Troponin T / Q000235:genetics / Q000378:metabolism*; D014463:Ultrasonography
chemical_list: C431578:Nppa protein, mouse; D011498:Protein Precursors; D020107:Troponin T; D020098:Natriuretic Peptide, C-Type; D009320:Atrial Natriuretic Factor; D000251:Adenosine Triphosphatases; D002118:Calcium