Inhibition of tumor necrosis factor-alpha reduces atherosclerosis in apolipoprotein E knockout mice

Abstract

Objective: Inflammation plays an important role in atherosclerosis. One of the most potent pro-inflammatory cytokines is tumor necrosis factor-alpha (TNF-alpha), a cytokine identified to have a pathogenic role in chronic inflammatory diseases such as rheumatoid arthritis (RA). The aim of the study was to evaluate the importance of TNF-alpha in atherogenesis.

Methods and results: Mice deficient in both apolipoprotein E (apoE) and TNF-alpha were compared regarding their atherosclerotic burden. Mice were fed a Western-style diet (WD) or normal chow. Mice deficient in both apoE and TNF-alpha exhibited a 50% (P=0.035) reduction of relative lesion size after 10 weeks of WD. Bone marrow transplantation of apoE(o) mice with apoE(o)tnf-alpha(o) bone marrow resulted in a 83% (P=0.021) reduction after 25 weeks on WD. In apoE knockout mice treated with recombinant soluble TNF receptor I releasing pellets, there was a reduction in relative lesion size after 25 weeks of 75% (P=0.018).

Conclusions: These findings demonstrate that TNF-alpha is actively involved in the progression of atherosclerosis. Accordingly, TNF-alpha represents a possible target for prevention of atherosclerosis. This may be of particular importance in rheumatoid arthritis because these patients have an increased risk for cardiovascular disease.