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.
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.
Park
Su-Young
SY
College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Korea.
Lee
Jong-Suk
JS
Ko
Yu Jin
YJ
Kim
Ah Ra
AR
Choi
Mi Kyoung
MK
Kwak
Mi-Kyoung
MK
Choi
Han Gon
HG
Yong
Chul Soon
CS
Kim
Jung-Ae
JA
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
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