Novel TNF-α Receptor 1 Antagonist Treatment Attenuates Arterial Inflammation and Intimal Hyperplasia in Mice

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    • Isoda Kikuo
    • Internal Medicine I, National Defense Medical College.
    • Kamada Haruhiko
    • Laboratory of Biopharmaceutical Research, National Institute of Biomedical Innovation.
    • Tsunoda Shinichi
    • Laboratory of Biopharmaceutical Research, National Institute of Biomedical Innovation.
    • Tsutsumi Yasuo
    • Laboratory of Biopharmaceutical Research, National Institute of Biomedical Innovation.|Department of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University.


Aim: Tumor necrosis factor receptor 1 (TNFR1) participates importantly in arterial inflammation in genetically altered mice; however it remains undetermined whether a selective TNFR1 antagonist inhibits arterial inflammation and intimal hyperplasia. This study aimed to determine the effect and mechanism of a novel TNFR1 antagonist in the suppression of arterial inflammation.<BR>Methods: We investigated intimal hyperplasia in IL-1 receptor antagonist-deficient mice two weeks after inducing femoral artery injury in an external vascular cuff model. All mice received intraperitoneal injections of TNFR1 antagonist (PEG-R1antTNF) or normal saline twice daily for 14 days.<BR>Results: PEG-R1antTNF treatment yielded no adverse systemic effects, and we observed no significant differences in serum cholesterol or blood pressure in either group; however, selective PEG-R1antTNF treatment significantly reduced intimal hyperplasia (19,671±4,274 vs. 11,440±3,292 µm<sup>2</sup>; <i>p</i>=0.001) and the intima/media ratio (1.86±0.43 vs. 1.34±0.36; <i>p</i>=0.029), compared with saline injection. Immunostaining revealed that PEG-R1antTNF inhibits Nuclear factor-κB (NF-κB), suppressing smooth muscle cell (SMC) proliferation and decreasing chemokine and adhesion molecule expression, and thus decreasing intimal hyperplasia and inflammation.<BR>Conclusions: Our data suggest that PEG-R1antTNF suppresses SMC proliferation and inflammation by inhibiting NF-κB. This study highlights the potential therapeutic benefit of selective TNFR1 antagonist therapy in preventing intimal hyperplasia and arterial inflammation.


  • Journal of Atherosclerosis and Thrombosis

    Journal of Atherosclerosis and Thrombosis 19(1), 36-46, 2012

    Japan Atherosclerosis Society


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