The cytoprotective effects of tumor necrosis factor are conveyed through tumor necrosis factor receptor-associated factor 2 in the heart

Jana S. Burchfield, Jian Wen Dong, Yasushi Sakata, Feng Gao, Huei Ping Tzeng, Veli K. Topkara, Mark L. Entman, Natarajan Sivasubramanian, Douglas L. Mann

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Background:Activation of both type 1 and type 2 tumor necrosis factor (TNF) receptors (TNFR1 and TNFR2) confers cytoprotection in cardiac myocytes. Noting that the scaffolding protein TNF receptor-associated factor 2 (TRAF2) is common to both TNF receptors, we hypothesized that the cytoprotective responses of TNF were mediated through TRAF2. Methods and Results:Mice with cardiac-restricted overexpression of low levels of TNF (MHCsTNF3) and TRAF2 (MHC-TRAF2LC) and mice lacking TNFR1, TNFR2, and TNFR1/TNFR2 were subjected to ischemia (30 minutes) reperfusion (30 minutes) injury ex vivo using a Langendorff apparatus. MHCsTNF3 mice were protected against ischemia-reperfusion injury as shown by a significant ≈30% greater left ventricular developed pressure, ≈80% lower creatine kinase release, and Evans blue dye uptake compared with littermates. The extent of ischemia-reperfusion induced injury was similar in wild-type, TNFR1, and TNFR2 deficient mice; however, mice lacking TNFR1/TNFR2 had a significant ≈40% lower left ventricular developed pressure, a ≈65% greater creatine kinase release, and ≈40% greater Evans blue dye uptake compared with littermates. Interestingly, MHC-TRAF2LC mice had a significant ≈50% lower left ventricular developed pressure, a ≈70% lower creatine kinase release, and ≈80% lower Evans blue dye uptake compared with littermate controls after ischemia-reperfusion injury. Biochemical analysis of the MHC-TRAF2LC hearts showed that there was activation of nuclear factor-kappaB but not c-Jun N-terminal kinase activation. Conclusion:Taken together, these results suggest that TNF confers cytoprotection in the heart through TRAF2-mediated activation of nuclear factor-KB.

Original languageEnglish
Pages (from-to)157-164
Number of pages8
JournalCirculation: Heart Failure
Volume3
Issue number1
DOIs
StatePublished - Jan 2010

Keywords

  • Ischemia-reperfusion injury
  • Tumor necrosis factor
  • Tumor necrosis factor receptor-associated factor 2

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