Abstract 11413: TNF-α Receptor 1 Antagonist Treatment Attenuates Arterial Inflammation and Intimal Hyperplasia in Interleukin-1 Receptor Antagonist Deficient Mice
Background: Tumor necrosis factor (TNF)-α plays a key role in arterial inflammation. We have shown that TNF-α participates importantly in the development of aortitis and intimal hyperplasia in IL-1 receptor antagonist-deficient (IL-1Ra−/−) mice. However it remains undetermined whether a selective TNF receptor 1 (TNFR1) antagonist inhibits arterial inflammation and intimal hyperplasia. This study aimed to determine the effect and mechanism of a novel TNFR1 antagonist (PEG-R1antTNF) in the suppression of arterial inflammation.
Methods and Results: We investigated intimal hyperplasia in IL-1Ra−/− mice two weeks after inducing femoral artery injury with an external vascular cuff model. We injected mice intraperitoneally with a PEG-R1antTNF or normal saline twice daily for 14days. PEG-R1antTNF treatment yielded no adverse systemic effects, and we observed no significant differences in serum cholesterol or blood pressure in either group. Compared to saline injection, however, selective PEG-R1antTNF treatment significantly reduced intimal hyperplasia (11,440 ± 3,292 vs. 19,671 ± 1,625μm2; P=0.011) and intima/media ration (1.34 ± 0.14 vs. 1.86 ± 0.16 ; P=0.029). Immunostaining revealed that inhibition of NF-κB activation by PEG-R1antTNF suppressed smooth muscle cell (SMC) proliferation and decreased expression of chemokine and adhesion molecules. Furthermore, immunostaining also revealed fewer macrophages in the intima of PEG-R1antTNF treated mice compared with controls. These results showed that PEG-R1antTNF decreased inflammation and intimal hyperplasia in the injured artery of IL-1Ra−/− mice.
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. Furthermore, PEG-R1antTNF therapy may have a lower risk for infection compared with nonselective anti-TNF therapy, because previous study suggested that TNFR2-facilitated programmed necrosis may have a crucial role in regulating immune responses against bacterial and viral infection.
- © 2010 by American Heart Association, Inc.