Raloxifene-mediated increase in matrix metalloproteinase-1 production by activated monocytes.
Matrix metalloproteinases (MMPs), proteolytic enzymes produced by monocytes, may contribute to atherosclerotic arterial wall remodeling and to plaque rupture. Because estrogen influences the synthesis of MMPs, we examined the effect of raloxifene, a selective estrogen receptor modulator, on monocyte MMP production. Human primary blood monocytes treated with raloxifene (10 micromol/L) in the presence of lipopolysaccharide (LPS) or tumor necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor induced a 2- to 3-fold increase in MMP-1 production by monocytes. The enhancement of MMP-1 production by raloxifene in LPS-activated monocytes occurred through a cyclooxygenase-2- and prostaglandin E(2)-independent mechanism. Additionally, compared with monocytes acquired during the placebo phase, peripheral blood monocytes from 5 of 6 healthy postmenopausal women treated with raloxifene (60 mg daily for 1 month) in a clinical trial produced significantly higher levels of MMP-1 when the monocytes were activated with LPS. Furthermore, serum obtained during the raloxifene phase from 4 of these subjects, when added to control monocytes, significantly enhanced LPS-induced MMP-1 production compared with that from serum obtained during the placebo phase. In summary, raloxifene increases the production of MMP-1 in activated monocytes; this effect may be favorable in atherosclerotic arterial wall remodeling but unfavorable for plaque stability.
Ardans
J A
JA
Immunopathology Section, National Institute of Dental and Craniofacial Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Blum
A
A
Mangan
P R
PR
Wientroub
S
S
Cannon
R O
RO
Wahl
L M
LM
D001161:Arteriosclerosis / Q000097:blood*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D004311:Double-Blind Method; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis* / Q000378:metabolism; D008565:Membrane Proteins; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D017698:Postmenopause; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D020849:Raloxifene Hydrochloride / Q000494:pharmacology* / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D020845:Selective Estrogen Receptor Modulators; D014409:Tumor Necrosis Factor-alpha; D020849:Raloxifene Hydrochloride; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020781:Matrix Metalloproteinase 1; D015232:Dinoprostone