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.
Panagopoulou
Panagiota
P
Cell Biology Division, Center of Basic Research, and 2Cardiovascular Research Division, Center of Clinical Research, Biomedical Research Foundation, Academy of Athens, Athens 11527, Greece.
Davos
Constantinos H
CH
Milner
Derek J
DJ
Varela
Emily
E
Cameron
Joann
J
Mann
Douglas L
DL
Capetanaki
Yassemi
Y
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