Abstract 13892: The Cytoprotective Effects of Tumor Necrosis Factor Are Mediated by Dysferlin: An Emergency Response Gene that Mediates Membrane Repair
Background: The cytoprotective effects of tumor necrosis factor in cardiac ischemia reperfusion (IR) injury are mediated by tumor necrosis factor receptor associated factor 2 (TRAF2).
Methods: To delineate the mechanism(s) for the cytoprotective effects downstream from TRAF2 signaling, we performed a gene array in mouse hearts with cardiac-restricted overexpression of TRAF2 (MHC-TRAF2LC), dominant negative TRAF2 (MHC-TRAF2DN), and littermate controls (LMs).
Results: Of the ∼25,000 genes examined, there were 124 significant genes that were both up-regulated in MHC-TRAF2LC hearts and down-regulated in the MHC-TRAF2DN hearts compared to LMs. Gene ontology based on cell components identified plasma membrane genes as a major group of bi-directionally regulated genes.. By focusing on genes that were responsible for membrane integrity in cardiac myocytes, we identified the candidate gene: dysferlin (Dysf). Dysf mRNA levels were up-regulated in MHC-TRAF2LC hearts. Dysf protein levels were increased in MHC-TRAF2LC hearts and decreased in MHC-TRAF2DN hearts. Hearts from Dysf-null mice were subjected to IR injury using a Langendorff apparatus (Figure). LV injury was assessed by measuring % recovery of LV developed pressure (%LVDP) compared to baseline. There was a significant increase in %LVDP after IR injury in Dysf-null hearts compared to wild-type (WT) hearts. Both creatine kinase release and Evans blue dye uptake were significantly greater in the IR-injured Dysf-null hearts compared with WTs, suggesting that dysferlin confers cytoprotection in the heart. Furthermore, the cytoprotective effects of TRAF2 were attenuated in the hearts from MHC-TRAF2LC mice crossbred with Dysf-null mice.
Conclusions: Viewed together, these results suggest that the cytoprotective effects of TRAF2 are mediated, at least in part, through a mechanism that involves dysferlin-mediated plasma membrane repair.
- © 2010 by American Heart Association, Inc.