Rosuvastatin reduces MMP-7 secretion by human monocyte-derived macrophages: potential relevance to atherosclerotic plaque stability.
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to reduce cardiovascular morbidity and mortality by their actions on atherogenic lipid profiles and by pleiotropic effects. In this study, we have investigated the effect of a new statin, rosuvastatin (Crestor), on sterol synthesis and the expression of metalloproteinases (MMPs) in human monocyte-derived macrophages (HMDM). Rosuvastatin dose-dependently inhibited sterol synthesis from acetate with an IC(50) of 70 nM. In addition, MMP-7 levels were reduced in a dose-dependent manner with maximal inhibition of 50% (P < 0.01) at 1 microM. Also, addition of isoprenoids such as farnesyl pyrophosphate (Fpp) or geranylgeranyl pyrophosphate (GGpp) fully overcame the inhibitory effect of rosuvastatin on MMP-7. Neither quantitative PCR nor transient transfection of HMDM with a luciferase reporter construct under the control of human MMP-7 promoter (2300 bp of the 5' region on MMP-7 gene) showed a decrease in MMP-7 mRNA following treatment with rosuvastatin (10(-6)M). However, the inhibitory effect of the statin occurred at the post-transcriptional level as determined by actinomycin D experiment. In conclusion, several studies have reported a high expression of active MMP-7 in human atherosclerotic plaques indicating a potential role in the weakening of the fibrous cap, predisposing it to rupture. The effect of rosuvastatin in reducing MMP-7 might protect fibrous caps from degradation and in turn stabilize atheromatous plaques.
Furman
Christophe
C
INSERM U-545 and Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 245, 59019 Lille Cedex, France.
Copin
Corinne
C
Kandoussi
Mejid
M
Davidson
Robert
R
Moreau
Martine
M
McTaggiart
Fergus
F
Chapman
M John
MJ
Fruchart
Jean-Charles
JC
Rouis
Mustapha
M
D001161:Arteriosclerosis / Q000503:physiopathology; D001483:Base Sequence; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005464:Fluorobenzenes / Q000494:pharmacology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000187:drug effects* / Q000378:metabolism; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D012016:Reference Values; D000068718:Rosuvastatin Calcium; D012680:Sensitivity and Specificity; D013449:Sulfonamides / Q000494:pharmacology*
D005464:Fluorobenzenes; D011743:Pyrimidines; D012333:RNA, Messenger; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D020783:Matrix Metalloproteinase 7