Dysferlin Mediates the Cytoprotective Effects of TRAF 2 Following Myocardial Ischemia Reperfusion Injury

HP Tzeng, S Evans, F Gao, K Chambers… - Journal of the …, 2014 - Am Heart Assoc
HP Tzeng, S Evans, F Gao, K Chambers, VK Topkara, N Sivasubramanian, PM Barger…
Journal of the American Heart Association, 2014Am Heart Assoc
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 …
Background
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.
Methods/Results
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.
Conclusion
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.
Am Heart Assoc