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Cardiovascular Research Advance Access originally published online on March 18, 2008
Cardiovascular Research 2008 79(1):109-117; doi:10.1093/cvr/cvn078
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Differential interactions of thin filament proteins in two cardiac troponin T mouse models of hypertrophic and dilated cardiomyopathies

Raffaella Lombardi1, Achim Bell1, Vinitha Senthil1, Jasvinder Sidhu3, Michela Noseda3, Robert Roberts4 and Ali J. Marian1,2,*

1 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
2 Texas Heart Institute, Houston, TX 77030, USA
3 Section of Cardiology, Baylor College of Medicine, Houston, TX 77030, USA
4 University of Ottawa Heart Institute, Ottawa, Canada

* Corresponding author. Tel: +1713 500 2350 ; fax: +1 713 500 2320. E-mail address: ali.j.marian{at}uth.tmc.edu

Aim: 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.

Methods and 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.

Conclusion: Differential interactions among the sarcomeric proteins containing cTnT-Q92 or cTnT-W141 are responsible for the contrasting phenotypes of HCM or DCM, respectively.

KEYWORDS Cardiomyopathy; Genetics; Mutation; Mouse model; Pathogenesis; Fibrosis; Heart failure

Time for primary review: 22 days


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