Disruption of tumor necrosis factor-α gene diminishes the development of atherosclerosis in ApoE-deficient mice

Inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha) have been implicated in atherogenesis. However, the precise role of TNF-alpha in atherogenesis is still unclear. To examine the effect of TNF-alpha on atherogenesis, we generated compound-deficient mice in apolipoprotein E (apoE) and TNF-alpha (apoE(-/-)/TNF-alpha(-/-)) and compared them with apoE(-/-) mice. Although serum total cholesterol levels were markedly elevated in both apoE(-/-)/TNF-alpha(-/-) and apoE(-/-) mice compared to wild-type mice, no differences were observed between apoE(-/-)/TNF-alpha/(-/-) and apoE(-/-) mice. The atherosclerotic plaque area in the aortic luminal surface of apoE(-/-)/TNF-alpha(-/-) mice (n = 8, 3.1 +/- 0.4%) was significantly smaller than that of apoE(-/-) mice (n = 7, 4.7 +/- 0.4%, p < 0.001) despite the lack of difference in serum cholesterol levels. The atherosclerotic lesion size in the aortic sinus of apoE(-/-) /TNF-alpha(-/-) mice (n = 10, 5.1 +/- 0.3 x 10(5) mu m(2)) was also significantly smaller than that of apoE(-/-) mice (n = 11, 7.0 +/- 0.3 x 10(5) mu m(2), p < 0.0001). RT-PCR analysis indicated that the expression levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) were significantly higher in apoE(-/-) than apoE(-/-)/TNF-alpha(-/)- mice. Macrophages from apoE(-/-) mice showed higher uptake level of oxidized LDL and increased expression level of scavenger receptor class A (SRA) compared to those from apoE(-/-)/TNF-alpha(-/-) mice. These results indicate that TNF-alpha plays an atherogenic role by upregulating the expressions of ICAM-1, VCAM-1 and MCP-1 in the vascular wall, and by inducing SRA expression and oxidized LDL uptake in macrophages. (c) 2004 Elsevier Ireland Ltd. All rights reserved.