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

Inflammatory cytokines, including tumor necrosis factor-α (TNF-α) have been implicated in atherogenesis. However, the precise role of TNF-α in atherogenesis is still unclear. To examine the effect of TNF-α on atherogenesis, we generated compound-deficient mice in apolipoprotein E (apoE) and TNF-α (apoE^-/-/TNF-α ^-/-) and compared them with apoE^-/- mice. Although serum total cholesterol levels were markedly elevated in both apoE^-/-/TNF- α^-/- and apoE^-/- mice compared to wild-type mice, no differences were observed between apoE^-/-/TNF-α^-/- and apoE^-/- mice. The atherosclerotic plaque area in the aortic luminal surface of apoE^-/-/TNF-α^-/- 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-α^-/- mice (n = 10, 5.1 ± 0.3 × l0⁵ μm²) was also significantly smaller than that of apoE^-/- mice (n = 11, 7.0 ± 0.3 × l0⁵ μm², 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- α^-/- 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- α^-/- mice. These results indicate that TNF-α 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.