title: Dysferlin mediates the cytoprotective effects of TRAF2 following myocardial ischemia reperfusion injury.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Huei-Ping
authors.initials: HP
authors.lastname: Tzeng
authors.forename: Sarah
authors.initials: S
authors.lastname: Evans
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Kari
authors.initials: K
authors.lastname: Chambers
authors.forename: Veli K
authors.initials: VK
authors.lastname: Topkara
authors.forename: Natarajan
authors.initials: N
authors.lastname: Sivasubramanian
authors.forename: Philip M
authors.initials: PM
authors.lastname: Barger
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Mann
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D002463:Cell Membrane Permeability; D003402:Creatine Kinase / Q000097:blood; D004195:Disease Models, Animal; D000073939:Dysferlin; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005838:Genotype; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
chemical_list: D015415:Biomarkers; C497505:Dysf protein, mouse; D000073939:Dysferlin; D008565:Membrane Proteins; D047992:TNF Receptor-Associated Factor 2; D003402:Creatine Kinase
keywords: TNF receptor associated factor 2; cytoprotection; dysferlin; tumor necrosis factor