EXPERIMENTAL STUDY
Improved myocardial ischemia/reperfusion injury in mice lacking tumor necrosis factor-
Naoya Maekawa, BSc*,
Hisayasu Wada, MD, PhD*,*,
Tsugiyasu Kanda, MD, PhD ,
Tamikazu Niwa, BSc*,
Yasuhiro Yamada, MD, PhD*,
Kuniaki Saito, PhD*,
Hisayoshi Fujiwara, MD, PhD ,
Kenji Sekikawa, PhD and
Mitsuru Seishima, MD, PhD*
* Department of Laboratory Medicine, Gifu University School of Medicine, Gifu, Japan
Second Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan
Department of Laboratory Medicine, Gunma University School of Medicine, Maebashi, Japan
Department of Immunology, National Institute of Animal Health, Tsukuba, Japan
Manuscript received February 28, 2001;
revised manuscript received January 2, 2002,
accepted January 11, 2002.
* Reprint requests and correspondence: Dr. Hisayasu Wada, Department of Laboratory Medicine, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu City, Gifu 500-8705, Japan.
wadah{at}cc.gifu-u.ac.jp
OBJECTIVES: This study sought to assess the role of tumor necrosis factor- (TNF-) in myocardial ischemia/reperfusion (I/R) injury using TNF- knockout (KO) mice.
BACKGROUND: Tumor necrosis factor- is thought to be involved in the pathogenesis of myocardial I/R injury by promoting leukocyte infiltration of the myocardium. However, the precise role of TNF- in I/R injury is still unknown.
METHODS: The hearts in TNF- KO and wild-type (WT) mice were exposed by left lateral thoracotomy, and the left coronary artery was occluded for 30 min then reperfused for 120 min.
RESULTS: The infarct size in TNF- KO mice was significantly reduced compared with WT mice. The frequency of arrhythmia was decreased, and cardiac function during reperfusion was significantly improved in TNF- KO mice compared with WT mice. The activation of nuclear factor- B (NF-B), the expression of chemokines and adhesion molecules and the infiltration of leukocytes were also significantly reduced in TNF- KO mice, compared with WT mice. These findings provide evidence that TNF- aggravates I/R injury.
CONCLUSIONS: Tumor necrosis factor- exacerbates myocardial I/R injury at an early stage of reperfusion by activating NF-B, thereby inducing chemokines and adhesion molecules and facilitating leukocyte infiltration.
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Abbreviations and Acronyms
| | AAR | | area at risk | | IA | | infarct area | | ICAM | | intercellular adhesion molecule | | IL | | interleukin | | I/R | | ischemia/reperfusion | | KO | | knockout | | LV | | left ventricle | | MCP | | monocyte chemoattractant protein | | MIP | | macrophage inflammatory protein | | NF-B | | nuclear factor-B | | RT-PCR | | reverse transcription and polymerase chain reaction | | TNF- | | tumor necrosis factor- | | WT | | wild-type |
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