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

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.