Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
9157801 | Atherosclerosis | 2005 | 7 Pages |
Abstract
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 (apoEâ/â/TNF-αâ/â) and compared them with apoEâ/â mice. Although serum total cholesterol levels were markedly elevated in both apoEâ/â/TNF-αâ/â and apoEâ/â mice compared to wild-type mice, no differences were observed between apoEâ/â/TNF-αâ/â and apoEâ/â mice. The atherosclerotic plaque area in the aortic luminal surface of apoEâ/â/TNF-αâ/â mice (n = 8, 3.1 ± 0.4%) was significantly smaller than that of apoEâ/â 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 apoEâ/â/TNF-αâ/â mice (n = 10, 5.1 ± 0.3 Ã l05 μm2) was also significantly smaller than that of apoEâ/â mice (n = 11, 7.0 ± 0.3 Ã 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 apoEâ/â than apoEâ/â/TNF-αâ/â mice. Macrophages from apoEâ/â mice showed higher uptake level of oxidized LDL and increased expression level of scavenger receptor class A (SRA) compared to those from apoEâ/â/TNF-αâ/â 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.
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Authors
Hirotoshi Ohta, Hisayasu Wada, Tamikazu Niwa, Hirokazu Kirii, Naoki Iwamoto, Hidehiko Fujii, Kuniaki Saito, Kenji Sekikawa, Mitsuru Seishima,