Journal
CIRCULATION-HEART FAILURE
Volume 3, Issue 1, Pages 157-164Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCHEARTFAILURE.109.899732
Keywords
ischemia-reperfusion injury; tumor necrosis factor; tumor necrosis factor receptor-associated factor 2
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Funding
- National Institutes of Health [RO1 HL58081, RO1 HL61543, RO1 HL-42250, HL 076661, HL 089792]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL042250, R01HL076661, R01HL089792, R01HL058081, R01HL061543] Funding Source: NIH RePORTER
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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-TRAF2(LC)) 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 approximate to 30% greater left ventricular developed pressure, approximate to 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 approximate to 40% lower left ventricular developed pressure, a approximate to 65% greater creatine kinase release, and approximate to 40% greater Evans blue dye uptake compared with littermates. Interestingly, MHC-TRAF2(LC) mice had a significant approximate to 50% lower left ventricular developed pressure, a approximate to 70% lower creatine kinase release, and approximate to 80% lower Evans blue dye uptake compared with littermate controls after ischemia-reperfusion injury. Biochemical analysis of the MHC-TRAF2(LC) 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-kappa B. (Circ Heart Fail. 2010; 3: 157-164.)
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