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

Hirotoshi Ohta, Hisayasu Wada, Tamikazu Niwa, Hirokazu Kirii, Naoki Iwamoto, Hidehiko Fujii, Kuniaki Saito, Kenji Sekikawa, Mitsuru Seishima

Research output: Contribution to journalArticle

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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 (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.

Original languageEnglish
Pages (from-to)11-17
Number of pages7
JournalAtherosclerosis
Volume180
Issue number1
DOIs
Publication statusPublished - 01-01-2005
Externally publishedYes

Fingerprint

Apolipoproteins E
Atherosclerosis
Tumor Necrosis Factor-alpha
Genes
Class A Scavenger Receptors
Vascular Cell Adhesion Molecule-1
Chemokine CCL2
Intercellular Adhesion Molecule-1
Macrophages
Cholesterol
Sinus of Valsalva
Atherosclerotic Plaques
Serum
Blood Vessels

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Ohta, Hirotoshi ; Wada, Hisayasu ; Niwa, Tamikazu ; Kirii, Hirokazu ; Iwamoto, Naoki ; Fujii, Hidehiko ; Saito, Kuniaki ; Sekikawa, Kenji ; Seishima, Mitsuru. / Disruption of tumor necrosis factor-α gene diminishes the development of atherosclerosis in ApoE-deficient mice. In: Atherosclerosis. 2005 ; Vol. 180, No. 1. pp. 11-17.
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Disruption of tumor necrosis factor-α gene diminishes the development of atherosclerosis in ApoE-deficient mice. / Ohta, Hirotoshi; Wada, Hisayasu; Niwa, Tamikazu; Kirii, Hirokazu; Iwamoto, Naoki; Fujii, Hidehiko; Saito, Kuniaki; Sekikawa, Kenji; Seishima, Mitsuru.

In: Atherosclerosis, Vol. 180, No. 1, 01.01.2005, p. 11-17.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Disruption of tumor necrosis factor-α gene diminishes the development of atherosclerosis in ApoE-deficient mice

AU - Ohta, Hirotoshi

AU - Wada, Hisayasu

AU - Niwa, Tamikazu

AU - Kirii, Hirokazu

AU - Iwamoto, Naoki

AU - Fujii, Hidehiko

AU - Saito, Kuniaki

AU - Sekikawa, Kenji

AU - Seishima, Mitsuru

PY - 2005/1/1

Y1 - 2005/1/1

N2 - 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.

AB - 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.

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