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Inhibitory effect of simvastatin on the TNF-α- and angiotensin II-induced monocyte adhesion to endothelial cells is mediated through the suppression of geranylgeranyl isoprenoid-dependent ROS generation

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Abstract

Vascular endothelial cell activation by cytokines and other pro-inflammatory mediators is an 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) II-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-α-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 II. These results suggest that monocyte adhesion to endothelial cells induced by TNF-α or Ang II is mediated via the geranylgeranyl isoprenoid-dependent generation of ROS, and that this is inhibited by simvastatin.

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  1. College of Pharmacy, Yeungnam University, Gyeongsan, 712-749, Korea

    Su-Young Park, Jong-Suk Lee, Yu Jin Ko, Ah Ra Kim, Mi Kyoung Choi, Mi-Kyoung Kwak, Han Gon Choi, Chul Soon Yong & Jung-Ae Kim

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  1. Su-Young Park
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Correspondence to Jung-Ae Kim.

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Park, SY., Lee, JS., Ko, Y.J. et al. Inhibitory effect of simvastatin on the TNF-α- and angiotensin II-induced monocyte adhesion to endothelial cells is mediated through the suppression of geranylgeranyl isoprenoid-dependent ROS generation. Arch. Pharm. Res. 31, 195–204 (2008). https://doi.org/10.1007/s12272-001-1141-2

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