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

Manabu Kitagaki; Kikuo Isoda; Haruhiko Kamada; Takayuki Kobayashi; Shinichi Tsunoda; Yasuo Tsutsumi; Tomiharu Niida; Takehiko Kujiraoka; Norio Ishigami; Miya Ishihara; Osamu Matsubara; Fumitaka Ohsuzu; Makoto Kikuchi

doi:10.5551/jat.9746

Original Article

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

Manabu Kitagaki, Kikuo Isoda, Haruhiko Kamada, Takayuki Kobayashi, Shinichi Tsunoda, Yasuo Tsutsumi, Tomiharu Niida, Takehiko Kujiraoka, Norio Ishigami, Miya Ishihara, Osamu Matsubara, Fumitaka Ohsuzu, Makoto Kikuchi

Author information

Manabu Kitagaki
Medical Engineering, National Defense Medical College.
Kikuo Isoda
Internal Medicine I, National Defense Medical College.
Haruhiko Kamada
Laboratory of Biopharmaceutical Research, National Institute of Biomedical Innovation.
Takayuki Kobayashi
Basic Pathology, National Defense Medical College.
Shinichi Tsunoda
Laboratory of Biopharmaceutical Research, National Institute of Biomedical Innovation.
Yasuo Tsutsumi
Laboratory of Biopharmaceutical Research, National Institute of Biomedical Innovation.
Department of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University.
Tomiharu Niida
Internal Medicine I, National Defense Medical College.
Takehiko Kujiraoka
Internal Medicine I, National Defense Medical College.
Norio Ishigami
Internal Medicine I, National Defense Medical College.
Miya Ishihara
Medical Engineering, National Defense Medical College.
Osamu Matsubara
Basic Pathology, National Defense Medical College.
Fumitaka Ohsuzu
Internal Medicine I, National Defense Medical College.
Makoto Kikuchi
Medical Engineering, National Defense Medical College.

Keywords: TNF receptor 1 antagonist, Cytokine, Inflammation, Intimal hyperplasia, Smooth muscle cell

JOURNAL OPEN ACCESS

2012 Volume 19 Issue 1 Pages 36-46

DOI https://doi.org/10.5551/jat.9746

View "Advance Publication" version (December 7, 2011).

Details

Abstract

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.
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.
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 µm²; p=0.001) and the intima/media ratio (1.86±0.43 vs. 1.34±0.36; p=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.
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.

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