Abstract 205: Dysfunction of the 19S Proteosome Contributes to Adverse Cardiac Remodeling in Mice With Cardiac Restricted Overexpression of Tumor Necrosis Factor
We have shown previously that mice with cardiac restricted overexression of tumor necrosis factor (sTNF mice) develop progressive cardiac remodeling. Given that the ubiquitin/ proteasome system regulates protein turnover in eukaryotic cells and is thereby a major factor in controlling cell cycle, apoptosis, signal transduction pathways, which are important in cardiac remodeling, the purpose of this study was to assess the function of 19S, 20S and 26S proteasome in sTNF mice and littermate control mice.
Results: Activity of the 26S proteasome was significantly suppressed in the hearts of the sTNF mice compared with the wild type littermates, and was detectable as early as 4-weeks of age. To explore the mechanism for the dysfunction of the 26S proteosome, we examined the activity of the 19S and 20S subunits. We observed cleavage of two subunits of the 19S regulatory complex of the proteasome, namely S1 and S10b, in the hearts of the sTNF mice. S1 is involved in the linking of the lid and the base of the 19S complex, while S10b is one of the six ATPase subunits in the base of the 19S complex. Interestingly, we observed that the expression of six subunits of the 20S core complex, β2, β2i, β3, β4, β5, and β7 were up-regulated in the hearts of the sTNF mice compared with the wild type littermate control mice. Despite the higher expression of the six β subunits in the 20S complex, we observed no difference in the 20S proteasome activity in hearts between the sTNF mice and the wild type littermate controls.
Conclusion: Taken together, these results suggest that cleavage of S1 and S10b might contribute to the low 26S proteasome activity in the hearts of the sTNF mice. Given that the 26S proteasome is responsible for degrading pro-apoptotic pathways, as well as turning off pro-fibrotic signaling (TGF-beta), these results suggest that dysfunction of the 26S proteasome might be one of the mechanisms underlying left ventricular remodeling in the setting of sustained inflammation.