Desmin mediates TNF-alpha-induced aggregate formation and intercalated disk reorganization in heart failure.
We explored the involvement of the muscle-specific intermediate filament protein desmin in the model of tumor necrosis factor alpha (TNF-alpha)-induced cardiomyopathy. We demonstrate that in mice overexpressing TNF-alpha in the heart (alpha-myosin heavy chain promoter-driven secretable TNF-alpha [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 beta-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 beta-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.
Cell Biology Division, Center of Basic Research, and 2Cardiovascular Research Division, Center of Clinical Research, Biomedical Research Foundation, Academy of Athens, Athens 11527, Greece.
Panagiota
P
Panagopoulou
Constantinos H
CH
Davos
Derek J
DJ
Milner
Emily
E
Varela
Joann
J
Cameron
Douglas L
DL
Mann
Yassemi
Y
Capetanaki
D000818:Animals; D017209:Apoptosis; D009202:Cardiomyopathies / Q000473:pathology; D053178:Caspase 6 / Q000378:metabolism; D003893:Desmin / Q000378:metabolism / Q000502:physiology*; D051180:Desmoplakins / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D025801:Ubiquitin / Q000737:chemistry; D051176:beta Catenin / Q000378:metabolism
D003893:Desmin; D051180:Desmoplakins; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D051176:beta Catenin; D053178:Caspase 6