Simvastatin inhibits C-reactive protein-induced pro-inflammatory changes in endothelial cells by decreasing mevalonate pathway products.
OBJECTIVE
The effects of HMG-CoA reductase inhibitors on C-reactive protein (CRP)-induced pro-inflammatory changes in endothelial cells remain unclear. We tested the hypothesis that simvastatin inhibited CRP-induced pro-inflammatory changes in endothelial cells by decreasing mevalonate pathway products.


METHODS
Human umbilical vein endothelial cells were incubated with CRP and measurement of CD32, nuclear factor kappaB (NF-kappaB) activation, vascular cell adhesion molecule-1 expression and monocyte adhesion assay were performed. The effects of simvastatin, siRNA against CD32 (siCD32) and mevalonate pathway products were also examined.


RESULTS
Pre-treatment with simvastatin significantly attenuated the CRP-induced CD32 expression and NF-kappaB activation in human umbilical vein endothelial cells. Simvastatin also decreased CRP-induced vascular cell adhesion molecule-1 expression and reduced monocyte adhesion on endothelial cells. The inhibitory effects of simvastatin were significantly reversed by adding mevalonate and geranylgeranyl pyrophosphate (GGPP), but not by adding farnesyl pyrophosphate. Pre-treatment with siCD32 also decreased CRP-induced CD32 expression and inhibitor of kappaB degradation. However, neither mevalonate nor GGPP reversed the effects of siCD32.


CONCLUSIONS
CRP-induced CD32 expression and NF-kappaB activation were attenuated by simvastatin. A decrease in mevalonate and subsequent GGPP contributes to the inhibitory effects of simvastatin. These findings may provide an explanation of using statins on patients with high serum CRP levels.
Liang
Yao-Jen
YJ
Institute of Pharmacology, National Taiwan University, Taipei, Taiwan.
Shyu
Kou-Gi
KG
Wang
Bao-Wie
BW
Lai
Ling-Ping
LP
D002097:C-Reactive Protein / Q000494:pharmacology* / Q000502:physiology; D002448:Cell Adhesion; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007249:Inflammation; D008798:Mevalonic Acid / Q000378:metabolism*; D009000:Monocytes / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D017452:Receptors, IgG / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology*; D014471:Umbilical Veins; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; D011106:Polyisoprenyl Phosphates; D034741:RNA, Small Interfering; D017452:Receptors, IgG; D012717:Sesquiterpenes; D019010:Vascular Cell Adhesion Molecule-1; C004808:farnesyl pyrophosphate; D002097:C-Reactive Protein; D019821:Simvastatin; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid