| First Author | Panagopoulou P | Year | 2008 |
| Journal | J Cell Biol | Volume | 181 |
| Issue | 5 | Pages | 761-75 |
| PubMed ID | 18519735 | Mgi Jnum | J:137038 |
| Mgi Id | MGI:3797676 | Doi | 10.1083/jcb.200710049 |
| Citation | Panagopoulou P, et al. (2008) Desmin mediates TNF-alpha-induced aggregate formation and intercalated disk reorganization in heart failure. J Cell Biol 181(5):761-75 |
| abstractText | 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. |
