Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:2137-2142
Published online before print September 2, 2004, doi: 10.1161/01.ATV.0000143933.20616.1b
Published online before print September 2, 2004, doi: 10.1161/01.ATV.0000143933.20616.1b
© 2004 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Inhibition of Tumor Necrosis Factor-
Reduces Atherosclerosis in Apolipoprotein E Knockout Mice
From the Department of Medicine (L.B., M.N., E.B., J.N., S.J.), University Hospital MAS, Lund University; the Department of Pharmacy (L.H.), The Danish University of Pharmaceutical Sciences; the Department of Cardiology (S.J.), University Hospital MAS, Lund University; and Lund Strategic Research Center for Stem Cell Biology and Cell Therapy (S.J.), Lund Universit.
Correspondence to Lena Brånén, Experimental Cardiovascular Research, Wallenberg Laboratory, Ing 46, Plan 1, University Hospital MAS, S-205 02 Malmö, Sweden. E-mail lena.branen{at}medforsk.mas.lu.se
Objective— Inflammation plays an important role in atherosclerosis. One of the most potent pro-inflammatory cytokines is tumor necrosis factor-
(TNF-), 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- in atherogenesis.
Methods and Results— Mice deficient in both apolipoprotein E (apoE) and TNF- were compared regarding their atherosclerotic burden. Mice were fed a Western-style diet (WD) or normal chow. Mice deficient in both apoE and TNF- exhibited a 50% (P=0.035) reduction of relative lesion size after 10 weeks of WD. Bone marrow transplantation of apoEo mice with apoEotnf-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- is actively involved in the progression of atherosclerosis. Accordingly, TNF- 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.
Atherosclerosis is an inflammatory disease. We have shown that deficiency in TNF- reduces atherosclerosis. This implies that TNF antagonizers are interesting candidates for testing in clinical studies of atherosclerosis prevention.
Key Words: atherosclerosis • genetically altered mice • TNF-
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