title: Tumor necrosis factor-alpha does not modulate ischemia/reperfusion injury in naïve myocardium but is essential for the development of late preconditioning.
abstract: The role of tumor necrosis factor (TNF)-alpha in myocardial ischemia/reperfusion injury remains controversial. We used homozygous TNF-alpha null mice (TNF-alpha(-/-)) to determine whether TNF-alpha modulates myocardial ischemia/reperfusion injury. Mice were subjected to a 30-min coronary occlusion followed by 24 h of reperfusion. When wild-type mice were preconditioned with six cycles of 4-min coronary occlusion/4-min reperfusion 24 h before the 30-min occlusion, infarct size was reduced from 58.6 +/- 1.9% of the risk region to 19.3 +/- 3.6%, indicating a late preconditioning (PC) effect. In non-preconditioned TNF-alpha(-/-) mice, infarct size was similar to that observed in wild-type mice (55.5 +/- 3.7%). However, in TNF-alpha(-/-) mice preconditioned with six occlusion/reperfusion cycles 24 h earlier, infarct size was not reduced (55.2 +/- 5.7%), indicating that the late PC protection against infarction was completely abolished. While minimal TNF-alpha immunoreactivity was detected in sham-operated hearts, extensive TNF-alpha expression was noted in the cytoplasm of cardiomyocytes in the ischemic/reperfused region 30 min after the PC ischemia. At 30 min after PC, wild-type mice exhibited increased DNA-binding activity of nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1) and nuclear translocation of p65, c-Jun and c-Fos; all of these changes were absent in TNF-alpha(-/-) mice. These data demonstrate that TNF-alpha does not modulate infarct size in the naïve (non-preconditioned) state but is essential for the development of the late phase of ischemic PC, possibly via the activation of NF-kappa B and AP-1 transcription factors.
authors.affiliation: Experimental Research Laboratory, Division of Cardiology, University of Louisville, and the Jewish Hospital Heart and Lung Institute, Louisville, KY 40292, USA.
authors.forename: Buddhadeb
authors.initials: B
authors.lastname: Dawn
authors.forename: Yiru
authors.initials: Y
authors.lastname: Guo
authors.forename: Arash
authors.initials: A
authors.lastname: Rezazadeh
authors.forename: Ou-Li
authors.initials: OL
authors.lastname: Wang
authors.forename: Adam B
authors.initials: AB
authors.lastname: Stein
authors.forename: Greg
authors.initials: G
authors.lastname: Hunt
authors.forename: Jai
authors.initials: J
authors.lastname: Varma
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Xuan
authors.forename: Wen-Jian
authors.initials: WJ
authors.lastname: Wu
authors.forename: Wei
authors.initials: W
authors.lastname: Tan
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhu
authors.forename: Roberto
authors.initials: R
authors.lastname: Bolli
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D006439:Hemodynamics; D006720:Homozygote; D007150:Immunohistochemistry; D007511:Ischemia; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D017202:Myocardial Ischemia; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015427:Reperfusion Injury; D012306:Risk; D015398:Signal Transduction; D013696:Temperature; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*
chemical_list: D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D004247:DNA