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KMID : 0620920020340060451
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Experimental & Molecular Medicine
2002 Volume.34 No. 6 p.451 ~ p.461
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Statin inhibits interferon-γ-induced expression of intercellular adhesion molecule-1 (ICAM-1) in vascular endothelial and smooth muscle cells
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Min Ho Shong/Hyo Kyun Chung
In Kyu Lee/Hyo Kyung Kang/Jae Mi Suh/Ho Kim/Ki Cheol Park/Dong Wook Kim/Young Kun Kim/Heung Kyu Ro/Min Ho Shong
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Abstract
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Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, known as statins, are widely used for primary and secondary prevention of coronary artery atherosclerosis. Pathogenesis of atherosclerosis is multistep processes where transendothelial migration of various leukocytes including monocytes is a crucial step. Interferon-γ(IFN-γ) contributes in this process by activating macrophages and T-lymphocytes, and by inducing adhesion molecules in vascular endothelial and smooth muscle cells. In this study we investigated the expression of intercellular cell adhesion molecule- 1 (ICAM-1) in transformed endothelial cell line ECV304 cells as influenced by lovastatin, tumor necrosis factor-α (TNF-α) and IFN-γ. Results show that lovastatin suppresses expression of ICAM-1 by inhibiting the IFN-γ-induced extracellular signal-regulated kinase (ERK) p44/p42-STAT1 signaling pathway. In cells treated with lovastatin and IFN-γ.ICAM-1 was expressed at a lower level than in cells treated with IFN-γ alone. However, lovastatin does not reduce TNF-α induced expression of ICAM-1. A similar result was observed in cells treated with the MEKK inhibitor PD98059 and IFN-γ. Cis-acting DNA sequence elements were identified in the 5'-flanking region of the ICAM-1 promoter that mediate inhibition by lovastatin; these sequences map to the IFN-γ activated site which also binds the STAT1 homodimer. However, lovastatin did not inhibit IFN-γ-mediated induction of the Y701 phosphorylated form of STAT1. But lovastatin does inhibit the IFN-γ-mediated phosphorylation of ERK1/ERK2 (T202/Y204) and S727 phosphorylation of STAT1. TNF-α does not induce phosphorylation of ERK1/ERK2 and S727 in ECV304 and smooth muscle cells. The results provide the evidences that statins may have beneficial effects by inhibiting IFN-γ action in atherosclerotic process.
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