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Desmin mediates TNF-–induced aggregate formation and intercalated disk reorganization in heart failure

¹ Cell Biology Division, Center of Basic Research, and ² Cardiovascular Research Division, Center of Clinical Research, Biomedical Research Foundation, Academy of Athens, Athens 11527, Greece
³ Department of Cell and Developmental Biology and ⁴ College of Medicine, Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801
⁵ Winters Center for Heart Failure Research, Baylor College of Medicine, Houston, TX 77030

Correspondence to Yassemi Capetanaki: ycapetanaki{at}bioacademy.gr

We explored the involvement of the muscle-specific intermediate filament protein desmin in the model of tumor necrosis factor (TNF-)–induced cardiomyopathy. We demonstrate that in mice overexpressing TNF- in the heart (–myosin heavy chain promoter-driven secretable TNF- [MHCsTNF]), desmin is modified, loses its intercalated disk (ID) localization, and forms aggregates that colocalize with heat shock protein 25 and ubiquitin. Additionally, other ID proteins such as desmoplakin and β-catenin show similar localization changes in a desmin-dependent fashion. To address underlying mechanisms, we examined whether desmin is a substrate for caspase-6 in vivo as well as the implications of desmin cleavage in MHCsTNF mice. We generated transgenic mice with cardiac-restricted expression of a desmin mutant (D263E) and proved that it is resistant to caspase cleavage in the MHCsTNF myocardium. The aggregates are diminished in these mice, and D263E desmin, desmoplakin, and β-catenin largely retain their proper ID localization. Importantly, D263E desmin expression attenuated cardiomyocyte apoptosis, prevented left ventricular wall thinning, and improved the function of MHCsTNF hearts.

Abbreviations used in this paper: DCM, dilated cardiomyopathy; DRM, desmin-related myopathy; EDD, end diastolic diameter; FS, fractional shortening; HSP, heat shock protein; ID, intercalated disk; IF, intermediate filament; LV, left ventricle; PWT, posterior wall thickness; UPS, ubiquitin proteasome system; WT, wild type.

© 2008 Panagopoulou et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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This article has been cited by other articles:

• Su, H., Wang, X. (2009). The ubiquitin-proteasome system in cardiac proteinopathy: a quality control perspective. Cardiovasc Res 0: cvp287v2-cvp287 [Abstract] [Full Text]  

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