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


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.
Brånén
Lena
L
Department of Medicine, University Hospital MAS, Experimental Cardiovascular Research, Wallenberg Laboratory, Ing 46, Plan 1, S-205 02 Malmö, Sweden. lena.branen@medforsk.mas.lu.se
Hovgaard
Lars
L
Nitulescu
Mihaela
M
Bengtsson
Eva
E
Nilsson
Jan
J
Jovinge
Stefan
S
D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000502:physiology; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism; D004343:Drug Implants / Q000494:pharmacology; D005260:Female; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000494:pharmacology; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000008:administration & dosage / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology
D001057:Apolipoproteins E; D004343:Drug Implants; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D008074:Lipoproteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D002784:Cholesterol