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

• Published in: Archives of pharmacal research 2008-02, Vol.31 (2), p.195-204
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Angiotensin II - antagonists & inhibitors; Angiotensin II - pharmacology; Cell Adhesion - drug effects; Cell Line; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Enzyme Activation - drug effects; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Medicine; Mevalonic Acid - pharmacology; Monocytes - drug effects; Monocytes - metabolism; NADPH Oxidases - metabolism; Pharmacology/Toxicology; Pharmacy; Polyisoprenyl Phosphates - pharmacology; Protein Prenylation - drug effects; Reactive Oxygen Species - metabolism; Simvastatin - pharmacology; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - pharmacology; Umbilical Veins - cytology; Umbilical Veins - drug effects; Umbilical Veins - metabolism
• ISSN: 0253-6269; 1976-3786
• DOI: 10.1007/s12272-001-1141-2

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.