Abstract 1009: TRAF2 Mediates Cytoprotective Signaling in Myocardial Ischemia Reperfusion Injury.
Background: Previous studies from this and other laboratories have shown that endogenous tumor necrosis factor (TNF) signaling confers cytoprotection in myocardial I/R injury via activation of TNF receptors 1 and 2. Noting that the TNF receptor associated factor 2 (TRAF2) was downstream from both TNF receptors, we hypothesized that TRAF2 mediated the cytoprotective effects of TNF during I/R injury.
Methods: We generated mice with cardiac-restricted overexpression of TRAF2 (MHC-TRAF2) or dominant negative TRAF2 (DNTRAF2). Hearts were subjected to ischemia (30 min) reperfusion (60 min) injury ex vivo using a buffer perfused Langendorff system. LV injury was assessed by measuring % recovery of LV developed pressure (%LVDP) compared to baseline, and by creatine kinase (CK) release. NF-κB activation was assessed by EMSA.
Results: Hearts from MHC-TRAF2 mice demonstrated a significant increase in %LVDP after I/R injury compared to WT controls (80.1 ± 6.3% vs. 63.2 ± 4.2%, p<0.05). In contrast, hearts of DNTRAF2 mice demonstrated a significant decrease in %LVDP after I/R injury compared to WT controls (41.2 ± 2.2% vs. 65.9 ± 3.7%, p<0.05), indicating TRAF2 improved LV functional recovery after IR injury. CK release was significantly reduced in MHC-TRAF2 mice compared to WT controls (5.8 ± 1.1 U/g vs. 22.2 ± 1.5 U/g, p<0.05), but was significantly increased in DNTRAF2 mice compared to WT controls (34.0 ± 2.9 U/g vs. 24.1 ± 2.7 U/g, p<0.05). NF-κB binding activity was increased in MHC-TRAF2 hearts but was down-regulated in DNTRAF2 hearts even after LPS challenge.
Conclusions: Taken together, these results suggest that TRAF2 confers cytoprotective responses in the heart following I/R injury.