Disruption of tumor necrosis factor-α gene diminishes the development of atherosclerosis in ApoE-deficient mice
| Autor: | Tamikazu Niwa, Hidehiko Fujii, Naoki Iwamoto, Hisayasu Wada, Hirotoshi Ohta, Kenji Sekikawa, Hirokazu Kirii, Kuniaki Saito, Mitsuru Seishima |
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| Rok vydání: | 2005 |
| Předmět: |
Male
Apolipoprotein E medicine.medical_specialty Necrosis Arteriosclerosis medicine.medical_treatment Gene Expression Vascular Cell Adhesion Molecule-1 Biology Proinflammatory cytokine Mice chemistry.chemical_compound Apolipoproteins E Internal medicine medicine Animals Scavenger receptor Aorta Chemokine CCL2 Triglycerides Tumor Necrosis Factor-alpha Cholesterol Monocyte Cholesterol HDL Intercellular Adhesion Molecule-1 Mice Mutant Strains Mice Inbred C57BL medicine.anatomical_structure Cytokine Endocrinology chemistry Female lipids (amino acids peptides and proteins) Tumor necrosis factor alpha medicine.symptom Cardiology and Cardiovascular Medicine |
| Zdroj: | Atherosclerosis. 180:11-17 |
| ISSN: | 0021-9150 |
| Popis: | 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%, p0.001) 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)microm(2)) was also significantly smaller than that of apoE-/- mice (n=11, 7.0+/-0.3 x 10(5)microm(2), p0.0001). 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. |
| Databáze: | OpenAIRE |
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