Tumor necrosis factor-α does not modulate ischemia/reperfusion injury in naïve myocardium but is essential for the development of late preconditioning

Buddhadeb Dawn, Yiru Guo, Arash Rezazadeh, Ou Li Wang, Adam B. Stein, Greg Hunt, Jai Varma, Yu Ting Xuan, Wen Jian Wu, Wei Tan, Xiaoping Zhu, Roberto Bolli

Research output: Contribution to journalArticlepeer-review

Abstract

The role of tumor necrosis factor (TNF)-α in myocardial ischemia/reperfusion injury remains controversial. We used homozygous TNF-α null mice (TNF-α-/-) to determine whether TNF-α 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-α-/- mice, infarct size was similar to that observed in wild-type mice (55.5 ± 3.7%). However, in TNF-α-/- 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-α immunoreactivity was detected in sham-operated hearts, extensive TNF-α 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-κB) and activator protein-1 (AP-1) and nuclear translocation of p65, c-Jun and c-Fos; all of these changes were absent in TNF-α-/- mice. These data demonstrate that TNF-α 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-κB and AP-1 transcription factors.

Original languageEnglish (US)
Pages (from-to)51-61
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume37
Issue number1
DOIs
StatePublished - Jul 1 2004

Keywords

  • Activator protein-1
  • Late preconditioning
  • Myocardial infarction
  • Nuclear factor-kappa B
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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