Abstract 3788: The Deleterious Effects of Tumor Necrosis Factor on Cardiac Remodeling Are Mediated by TNF Receptor Associated Factor 2
Previous studies have shown that cardiac restricted overexpression of tumor necrosis factor (TNF) leads to adverse left ventricular (LV) remodeling characterized by increased LV wall thinning and LV dilation. However, the signal transduction mechanism responsible for mediating TNF-induced adverse LV remodeling is not known. Noting that TNF receptor associated factor 2 (TRAF2) was downstream for both TNF receptors, we hypothesized that activation of TRAF2 mediates the effects of TNF on LV remodeling. To test this hypothesis we generated lines of transgenic mice with cardiac restricted overexpression of TRAF2 (MHC-TRAF2 mice) and examined their phenotype at 4, 8 and 12 wks of age. Compared to littermate (LM) controls, lines of MHC-TRAF2 with 24 copies of the transgene developed a dilated cardiac phenotype with a significant increase heart-to-body-weight ratio at 8 weeks (4.6 vs 4.3,p<0.001) and 12 weeks (5.3 vs 4.5,p<0.001) of age. 2D echo showed a significant increase in LV diameter, decreased fractional shortening and an increased r/h ratio in MHC-TRAF2 mice (all p < 0.01). Functional assessment of MHC-TRAF2 mice revealed decreased exercise capacity and increased oxygen consumption per unit work performed (p<0.05) compared to LM. Myocardial fibrosis was increased 2.1 fold at 8 wks and 4.4 fold at 12 wks(p<0.01) over LM in MHC-TRAF2 mice. There was also a sustained increase in JNK and NF-kB activity, as well as increased cardiac myocyte apoptosis in the MHC-TRAF2 mice at 4 and 8 weeks of age. These findings are similar to those observed in mice with targeted overexpession of TNF. Taken together, these data suggest that the deleterious effects of sustained TNF signaling are mediated through a TRAF2 dependent pathway, and suggest that blocking TRAF2 mediated signaling may prevent adverse LV remodeling in inflammatory cardiomyopathies.