Strong suppression of high-sensitivity C-reactive protein level and its mediated pro-atherosclerotic effects with simvastatin: in vivo and in vitro studies.
BACKGROUND
We hypothesize that high-sensitivity C-reactive protein (hs-CRP) levels and cell adhesion molecules (CAMs) significantly reflect serial changes in patients with atherosclerotic-risk factors undergoing simvastatin therapy. We further hypothesize that the site specificity of CRP on the expression of CAMs, which can be inhibited by simvastatin, is in the cytoplasm of endothelial cells (EC).


RESULTS
Serum hs-CRP levels and vascular (V) CAM-1 were measured (on days 0, 30, 90, 180 and 270) in 59 study subjects with at least one atherosclerotic-risk factor and low density lipoprotein (LDL) cholesterol >100 gm/dL. Simvastatin (40 mg/day) was given to each study subjects for 6 months. The inflammatory mediators were evaluated in 30 healthy subjects. Human umbilical vein (HUV) ECs were incubated with 1) culture medium alone, 2) added CRP for stimulation, and 3) simvastatin for 4 h before CRP was added. The hs-CRP and VCAM-1 levels were significantly higher on day 0 in study subjects than in healthy subjects (all p<0.0001). These inflammatory markers declined to a significantly lower level on day 90 (all p<0.001) and to an even lower level by day 180 (all p<0.0001). After simvastatin therapy was withdrawn, the hs-CRP level was once again significantly higher on day 270 than on day 180 (p<0.05), but VCAM-1 did not differ between day 180 and day 270. 25 micromol/L simvastatin markedly suppressed the CRP effect on VCAM-1 and intercellular CAM-1 expressions of EC. Immunocytochemical staining identified CRP in HUVEC cytoplasm. However, pretreatment with simvastatin reduced the intensity of CRP in cytoplasm.


CONCLUSIONS
CRP-mediated inflammation is inhibited by simvastatin.
Yip
Hon-Kan
HK
Division of Cardiology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Sun
Cheuk-Kwan
CK
Chang
Li-Teh
LT
Wu
Chiung-Jen
CJ
Chua
Sarah
S
Fu
Morgan
M
D000704:Analysis of Variance; D050197:Atherosclerosis / Q000097:blood / Q000517:prevention & control*; D015153:Blotting, Western; D002097:C-Reactive Protein / Q000032:analysis*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006949:Hyperlipidemias / Q000517:prevention & control; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D019821:Simvastatin / Q000627:therapeutic use*; D014471:Umbilical Veins / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D002097:C-Reactive Protein; D019821:Simvastatin