Suppression of neointimal hyperplasia after vascular injury by blocking 4-1BB/4-1BB ligand pathway

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  • Karube Akiyo
    Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan
  • Suzuki Jun-ichi
    Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan
  • Haraguchi Go
    Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan
  • Maejima Yasuhiro
    Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan
  • Saiki Hitoshi
    Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan
  • Kosuge Hisanori
    Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan
  • Isobe Mitsuaki
    Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan
  • Uede Toshimitsu
    Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Kita-ku, Sapporo, Japan.

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Abstract

Aim: T cell-mediated immunity is involved in the pathogenesis of atherosclerosis and arteriosclerosis. This study examined whether the 4-1BB pathway affects the development of arteriosclerosis after vascular injury. Methods and Results: The left or right femoral arteries of adult male mice weighing 22 to 25 g were injured with a straight spring wire. The injured artery was excised 28 days later. Confocal microscopy revealed intense expression of both 4-1BB and 4-1BBL in the developing neointima and media. Similar results were obtained on immunoblotting analysis of lysates of the injured arteries. We gave mice an injection of 100 μg or 200 μg 4-1BB-fused with human immunoglobulin (Ig) every other day over the course of 5 days. As compared with untreated controls (intima/media ratio, 2.13 ± 0.37, n=10), the intima/media ratio was smaller in mice treated with 200 μg of 4-1BBIg (1.20 ± 0.30, n=6, p<0.05), but not in mice treated with 100 μg of 4-1BBIg (1.56 ± 0.27, n=9). Conclusions: 4-1BB inhibits neointimal hyperplasia after vascular injury. Our fi ndings suggest that 4-1BB is involved in injury-induced neointimal hyperplasia and may be an effective target for the treatment of neointimal hyperplasia.

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