Dysferlin mediates the cytoprotective effects of TRAF2 following myocardial ischemia reperfusion injury.

ABSTRACT: We have demonstrated that tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2), a scaffolding protein common to TNF receptors 1 and 2, confers cytoprotection in the heart. However, the mechanisms for the cytoprotective effects of TRAF2 are not known.Mice with cardiac-restricted overexpression of low levels of TRAF2 (MHC-TRAF2LC) and a dominant negative TRAF2 (MHC-TRAF2DN) were subjected to ischemia (30-minute) reperfusion (60-minute) injury (I/R), using a Langendorff apparatus. MHC-TRAF2LC mice were protected against I/R injury as shown by a significant ?27% greater left ventricular (LV) developed pressure after I/R, whereas mice with impaired TRAF2 signaling had a significantly ?38% lower LV developed pressure, a ?41% greater creatine kinase (CK) release, and ?52% greater Evans blue dye uptake after I/R, compared to LM. Transcriptional profiling of MHC-TRAF2LC and MHC-TRAF2DN mice identified a calcium-triggered exocytotic membrane repair protein, dysferlin, as a potential cytoprotective gene responsible for the cytoprotective effects of TRAF2. Mice lacking dysferlin had a significant ?39% lower LV developed pressure, a ?20% greater CK release, and ?29% greater Evans blue dye uptake after I/R, compared to wild-type mice, thus phenocopying the response to tissue injury in the MHC-TRAF2DN mice. Moreover, breeding MHC-TRAF2LC onto a dysferlin-null background significantly attenuated the cytoprotective effects of TRAF2 after I/R injury.The study shows that dysferlin, a calcium-triggered exocytotic membrane repair protein, is required for the cytoprotective effects of TRAF2-mediated signaling after I/R injury.

SUBMITTER: Tzeng HP 

PROVIDER: S-EPMC3959693 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature