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

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 mu 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-kappa B (NF-kappa 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-kappa B. This study highlights the potential therapeutic benefit of selective TNFR1 antagonist therapy in preventing intimal hyperplasia and arterial inflammation.