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Cardiovascular Research Advance Access [Accepted Manuscript] published online on September 13, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn250
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Deficiency of Tumor Necrosis Factor-{alpha} and Interferon-{gamma} in Bone Marrow Cells Synergistically Inhibits Neointimal Formation Following Vascular Injury

Hideki Murayama, MD1, Masafumi Takahashi, MD, PhD1, Masaya Takamoto, PhD2, Yuji Shiba, MD, PhD1, Hirohiko Ise, PhD1, Jun Koyama, MD, PhD1, Yoh-ichi Tagawa, PhD3,4, Yoichiro Iwakura, PhD5 and Uichi Ikeda, MD, PhD1

1 Departments of Cardiovascular Medicine, Shinshu University Graduate School of Medicine, Matsumoto, Japan
2 Infection and Host Defense, Shinshu University Graduate School of Medicine, Matsumoto, Japan
3 Frontier Research Center, Tokyo Institute of Technology, Yokohama, Japan
4 Basic Research Programs PRESTO, Japan Science & Technology Agency, Japan
5 Institutee of Medical Science, University of Tokyo, Tokyo, Japan

Correspondence: Masafumi Takahashi, MD, PhD, Department of Cardiovascular Medicine, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan, Tel/ Fax: +81-263-37-3352/+81-263-37-2573, E-mail: masafumi{at}shinshu-u.ac.jp

Aims: Neointimal formation after percutaneous coronary intervention (PCI), termed restenosis, limits therapeutic revascularisation. Since it is now known that vascular injury involves inflammatory response, we examined the role of tumor necrosis factor-{alpha} (TNF-{alpha}) and interferon-{gamma} (IFN-{gamma}) in the neointimal formation after injury.

Methods and Results: Control (BALB/c), TNF-{alpha}-deficient (Tnf–/–), IFN-{gamma}-deficient (Ifng–/–), or double-deficient (Tnf–/–Ifng–/–) mice were subjected to wire-mediated vascular injury of the right femoral artery. Neointimal formation after injury was significantly reduced after the injury in the Tnf–/–Ifng–/– mice, compared to that in the control, Tnf–/–, and Ifng–/– mice. Immunohistochemical analysis showed that TNF-{alpha} and IFN-{gamma} were expressed in neointimal lesions in the control mice, but not in mice with deficiency of the corresponding cytokine. No significant difference in reendothelialisation was observed among these groups. The number of proliferating cell nuclear antigen (PCNA) in the neointimal lesions was significantly decreased in the Tnf–/–Ifng–/– mice. Bone marrow transplantation (BMT) experiments revealed that deficiency of TNF-{alpha} and IFN-{gamma} specifically in bone marrow cells significantly inhibited neointimal formation after vascular injury.

Conclusion: The absence of TNF-{alpha} and IFN-{gamma} in bone marrow cells synergistically inhibits neointimal formation following vascular injury, and thus, may provide new insights into the mechanisms underlying restenosis after PCI.

KEYWORDS bone marrow cell; cytokine; inflammation; restenosis

Time for primary review: 11 Days


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