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Cardiovascular Research Advance Access [Accepted Manuscript] published online on March 18, 2008
Cardiovascular Research, 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 Lombardi, Achim Bell, Vinitha Senthil, Jasvinder Sidhu{ddagger}, Michela Noseda{ddagger}, Robert Roberts and AJ Marian

Center for Cardiovascular Genetics, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center and Texas Heart Institute, Houston, TX 77030
{ddagger} Section of Cardiology, Baylor College of Medicine, Houston, TX 77030
University of Ottawa Heart Institute, Ottawa, Canada

Address for Correspondence and Reprints: AJ Marian, M.D. The Brown Foundation Institute of Molecular Medicine The University of Texas Health Sciences Center 6770 Bertner Street, Suite C900A Houston, TX 77030 Phone: 713 500 2350 (direct) and 713 500 2345 and 713 500 2312 (Indirect) Fax: 713 500 2320 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 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: We phenotyped the mice by echocardiography, histology and immunoblotting and RT-PCR. We detected interactions between the sarcomeric proteins by co-immunoprecipitation and determined Ca2+ sensitivity of myofibrillar protein ATPase activity by Carter assay.

Results: 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 as compared to 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.

Time for primary review: 22 days


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