Medical Engineering, National Defense Medical College, Saitama, Japan.
J Atheroscler Thromb. 2012;19(1):36-46. doi: 10.5551/jat.9746. Epub 2011 Dec 7.
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.
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.
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(2); 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.
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.
肿瘤坏死因子受体 1（TNFR1）在基因改变的小鼠动脉炎症中发挥重要作用；然而，尚不确定选择性 TNFR1 拮抗剂是否能抑制动脉炎症和内膜增生。本研究旨在确定新型 TNFR1 拮抗剂抑制动脉炎症的作用和机制。
我们在外周血管套管模型中研究了两周后白细胞介素-1 受体拮抗剂缺陷小鼠的股动脉损伤后内膜增生。所有小鼠均在腹腔内每日两次注射 TNFR1 拮抗剂（PEG-R1antTNF）或生理盐水，共 14 天。
PEG-R1antTNF 治疗无不良反应，两组血清胆固醇或血压均无显著差异；然而，选择性 PEG-R1antTNF 治疗可显著减少内膜增生（19671±4274μm(2)比 11440±3292μm(2)；p=0.001）和内膜/中膜比值（1.86±0.43 比 1.34±0.36；p=0.029），与生理盐水注射相比。免疫染色显示，PEG-R1antTNF 通过抑制核因子-κB（NF-κB）抑制平滑肌细胞（SMC）增殖，降低趋化因子和粘附分子的表达，从而减少内膜增生和炎症。
我们的数据表明，PEG-R1antTNF 通过抑制 NF-κB 抑制 SMC 增殖和炎症。本研究强调了选择性 TNFR1 拮抗剂治疗在预防内膜增生和动脉炎症中的潜在治疗益处。
