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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1265.)
© 2001 American Heart Association, Inc.

Vascular Biology

Raloxifene-Mediated Increase in Matrix Metalloproteinase-1 Production by Activated Monocytes

Jeanette A. Ardans; Arnon Blum; Paul R. Mangan; Shlomo Wientroub; Richard O. Cannon, III; Larry M. Wahl

From the Immunopathology Section (J.A.A., P.R.M., L.M.W.), National Institute of Dental and Craniofacial Research, and the Cardiology Branch (A.B., R.O.C.), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md, and the Department of Orthopedic Pediatrics (S.W.), Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Correspondence to Larry M. Wahl, PhD, NIDCR, National Institutes of Health, Building 30, Room 325, 30 Convent Dr, MSC 4352, Bethesda, MD 20892. E-mail lwahl{at}dir.nidcr.nih.gov

Abstract—— 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 µmol/L) in the presence of lipopolysaccharide (LPS) or tumor necrosis factor- 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 E₂–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.

Key Words: atherosclerosis • matrix metalloproteinases • monocytes • plaque • raloxifene

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