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 (+1 others)
2012 Journal of atherosclerosis and thrombosis  
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
more » ... rtery 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 m 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-B (NF-B), 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-B. This study highlights the potential therapeutic benefit of selective TNFR1 antagonist therapy in preventing intimal hyperplasia and arterial inflammation.
doi:10.5551/jat.9746 pmid:22146239 fatcat:mlv5a7kgyjhfrho6bkgm57daee