Published Online
on October 30, 2009

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Original Article

The Cytoprotective Effects of Tumor Necrosis Factor are Conveyed Through Tumor Necrosis Factor Receptor Associated Factor 2 in the Heart

Jana S. Burchfield¹; Jian-Wen Dong¹; Yasushi Sakata¹; Feng Gao¹; Huei-Ping Tzeng²; Veli K. Topkara²; Mark L. Entman¹; Natarajan Sivasubramanian¹ and Douglas L. Mann^2,3

¹ Baylor College of Medicine, Houston, TX;
² Washington University School of Medicine, St. Louis, MO; Baylor College of Medicine, Houston, TX

^* Corresponding author; email: dmann{at}dom.wustl.edu

Background—Activation of both the type 1 (TNFR1) and type 2 (TNFR2) tumor necrosis factor (TNF) receptor confers cytoprotection in cardiac myocytes. Noting that the scaffolding protein tumor necrosis factor 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 min) reperfusion (30 min) injury (I/R) ex vivo, using a Langendorff apparatus. MHC-sTNF₃ mice were protected against I/R injury as shown by a significant ~ 30 % greater LV developed pressure, and ~ 80% lower creatine kinase (CK) release and Evans blue dye uptake compared to littermates (LM). The extent of I/R induced injury was similar in wild-type, TNFR1 and TNFR2 deficient mice; however, mice lacking TNFR1/TNFR2 had a significant ~ 40% lower LV developed pressure, a ~ 65 % greater CK release and ~ 40% greater Evans blue dye uptake compared to LM. Interestingly, MHC-TRAF2_LC mice had a significant ~ 50 % lower LV developed pressure, a ~ 70% lower CK release and ~ 80% lower Evans blue dye uptake compared to LM controls following I/R injury. Biochemical analysis of the MHC-TRAF2_LC hearts showed that there was activation of NF-B but not JNK activation.

Conclusion—Taken together these results suggest that TNF confers cytoprotection in the heart through TRAF2 mediated activation of NF-B.

Key Words: ischemia reperfusion injury • tumor necrosis factor • tumor necrosis factor receptor associated factor 2