Dysferlin Mediates the Cytoprotective Effects of TRAF2 Following Myocardial Ischemia Reperfusion Injury

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Abstract
Background: We have demonstrated that tumor necrosis factor ( TNF ) receptor‐associated factor 2 ( TRAF 2), a scaffolding protein common to TNF receptors 1 and 2, confers cytoprotection in the heart. However, the mechanisms for the cytoprotective effects of TRAF 2 are not known. Methods/Results: Mice with cardiac‐restricted overexpression of low levels of TRAF 2 ( MHC ‐ TRAF 2 LC ) and a dominant negative TRAF 2 ( MHC ‐ TRAF 2 DN ) were subjected to ischemia (30‐minute) reperfusion (60‐minute) injury (I/R), using a Langendorff apparatus. MHC ‐ TRAF 2 LC 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 TRAF 2 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 ‐ TRAF 2 LC and MHC ‐ TRAF 2 DN mice identified a calcium‐triggered exocytotic membrane repair protein, dysferlin, as a potential cytoprotective gene responsible for the cytoprotective effects of TRAF 2. 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 ‐ TRAF 2 DN mice. Moreover, breeding MHC ‐ TRAF 2 LC onto a dysferlin‐null background significantly attenuated the cytoprotective effects of TRAF 2 after I/R injury. Conclusion: The study shows that dysferlin, a calcium‐triggered exocytotic membrane repair protein, is required for the cytoprotective effects of TRAF 2‐mediated signaling after I/R injury.

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