title: Inhibitory effect of simvastatin on the TNF-alpha- and angiotensin II-induced monocyte adhesion to endothelial cells is mediated through the suppression of geranylgeranyl isoprenoid-dependent ROS generation.
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)-alpha- 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-alpha-induced ROS and monocyte-endothelial cell adhesion, demonstrating that TNF-alpha-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 TNFalpha and Ang II. These results suggest that monocyte adhesion to endothelial cells induced by TNF-alpha or Ang II is mediated via the geranylgeranyl isoprenoid-dependent generation of ROS, and that this is inhibited by simvastatin.
authors: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Korea.
authors: Su-Young
authors: SY
authors: Park
authors: Jong-Suk
authors: JS
authors: Lee
authors: Yu Jin
authors: YJ
authors: Ko
authors: Ah Ra
authors: AR
authors: Kim
authors: Mi Kyoung
authors: MK
authors: Choi
authors: Mi-Kyoung
authors: MK
authors: Kwak
authors: Han Gon
authors: HG
authors: Choi
authors: Chul Soon
authors: CS
authors: Yong
authors: Jung-Ae
authors: JA
authors: Kim
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects*; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D019821:Simvastatin; D019255:NADPH Oxidases; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid