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KMID : 0043320080310020195
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Archives of Pharmacal Research
2008 Volume.31 No. 2 p.195 ~ p.204
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Inhibitory Effect of Simvastatin on the TNF-α- and Angiotensin Il-Induced Monocyte Adhesion to Endothelial Cells Is Mediated through the Suppression of Geranylgeranyl Isoprenoid-Dependent ROS Generation
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Park Su-Young
Lee Jong-Suk
Ko Yu-Jin
Kim Ah-Ra
Choi Mi-Kyoung
Kwak Mi-Kyoung
Choi Han-Gon
Yong Chul-Soon
Kim Jung-Ae
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Abstract
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Vascular endothelial cell activation by cytokines and other pro-inflammatory mediators is and initial event in atherosclerosis and in other vascular diseases. Simvastatin, a HMG-CoA reductase inhibitor, suppressed both tumor necrosis factor TNF-α- and angiotensin (Ang) Il-induced monocyte adhesion to endothelial cells (an initial step in vascular inflammation) and reactive oxygen species (ROS) production. Diphenyleneiodonium and apocynin, both NADPH oxidase inhibitors, also suppressed TNF--induced ROS and monocyte-endothelial cell adhesion, demonstrating that TNF-α-induced monocyte adhesion is mediated through ROS produced by NADPH oxidase activation. Furthermore, exogenously applied mevalonate or geranylgeranylpyrophosphate in combination with simvastatin completely prevented the inhibitory effects of simvastatin on ROS generation and monocyte-endothelial cell adhesion by TNF-α and Ang Il. These results suggest that monocyte adhesion to endothelial cells induced by TNF-α or Ang Il is mediated via the geranylgeranyl isoprenoid-dependent generation of ROS, and that this is inhibited by simvastatin.
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KEYWORD
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Reactive oxygen species, Tumor necrosis fadtor-α, Angiotensin Il, Mevalonate, Simvastatin, Monocyte-endothelial cell adhesion
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