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Potential mechanisms of the anti‐inflammatory effects of simvastatin in an in vitro flow model of inflammation
Author(s) -
Graham Anne,
Eccles Kirstie Alison,
Porter Karen,
HomerVanniasinkham Shervanthi
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1152-d
Subject(s) - simvastatin , geranylgeranyl pyrophosphate , histamine , farnesyl pyrophosphate , inflammation , prenylation , geranylgeranylation , statin , chemistry , pharmacology , stimulation , in vitro , biochemistry , biology , immunology , endocrinology , biosynthesis , enzyme
The endothelial cell (EC) adhesion molecule P‐selectin is crucial early in leukocyte recruitment during inflammation. Our laboratory has shown that simvastatin pre‐treatment prevents up‐regulation of P‐selectin under flow and this study aimed to investigate if ras or rho are mechanistically involved. Ras translocation from cytoplasm to membrane depends on farnesylation, that of Rho depends on geranylgeranylation. Effects of farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) to supplement respective pathways were investigated to determine if they reversed statin effects. HSVEC were seeded into 35mm dishes (2×105 cells/ml) until confluent and were pre‐treated with simvastatin +/− FPP and/or GGPP prior to histamine stimulation (5×10−4M;18min). Neutrophils (1×106 cells/ml) were perfused over EC in a glycotech flow chamber (1.1dyne cm2). EC:neutrophil interactions were recorded and counted. Histamine caused significant (p<0.001) increases in tethering. These effects were significantly (p<0.001) reduced to levels comparable to negative controls by pre‐treatment of EC with simvastatin (1μM;6h). FPP reversed statin effects by 36%, GGPP by 42% and the combination reversed effects by 89%. These results show that the down‐regulation of histamine mediated EC:leukocyte interactions in response to statin involves ras and rho signalling intermediates. Funded by Heart Research UK