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

Panagiota Panagopoulou, Constantinos H. Davos, Derek J. Milner, Emily Varela, Jo Ann Cameron, Douglas L. Mann, Yassemi Capetanaki

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

We explored the involvement of the muscles-pecific intermediate filament protein desmin in the model of tumor necrosis factor α (TNF-α)-induced cardiomyopathy. We demonstrate that in mice overexpressing TNF-α in the heart (α-myosin heavy chain promoter-driven secretable TNF-α [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.

Original languageEnglish
Pages (from-to)761-775
Number of pages15
JournalJournal of Cell Biology
Volume181
Issue number5
DOIs
StatePublished - Jun 2 2008
Externally publishedYes

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    Panagopoulou, P., Davos, C. H., Milner, D. J., Varela, E., Cameron, J. A., Mann, D. L., & Capetanaki, Y. (2008). Desmin mediates TNF-α-induced aggregate formation and intercalated disk reorganization in heart failure. Journal of Cell Biology, 181(5), 761-775. https://doi.org/10.1083/jcb.200710049