title: 17β-estradiol inhibits oxidized low-density lipoprotein-induced increase in matrix metalloproteinase-9 expression in human macrophages.
abstract: Beneficial effects of estrogen have been attributed to improved lipid profiles and to direct effects on the arterial wall. Macrophage-derived matrix metalloproteinases (MMPs) are expressed in atherosclerotic plaques, where they may contribute to plaque disruption. We have shown that oxidized low-density lipoprotein (Ox-LDL) increases matrix metalloproteinase-9 (MMP-9) expression in macrophages (Mφ). In this study, we tested the hypothesis that 17β-estradiol regulates basal and Ox-LDL-induced expression of MMPs and their tissue inhibitor (TIMPs) in human Mφ. Peripheral blood mononuclear cells isolated from normal human subjects were cultured for 7 days to transform into Mφ. On day 7, Mφ were starved with serum-free medium for 16 hours and then treated with 17β-estradiol and/or progesterone (PROG) in the presence or absence Ox-LDL for 24 hours. Levels and activity of MMP-2 and MMP-9 and levels of TIMP-1 and TIMP-2 were determined. After exposure to Ox-LDL, MMP-9 expression increased by 60% and TIMP-1 expression decreased by 29% (P < 0.05 and P < 0.05, respectively, compared to control), whereas TIMP-2 expression was unchanged. 17β-estradiol reduced the levels of Ox-LDL-induced MMP-9 protein as measured by Western blot (P < 0.05; n = 5) and Ox-LDL-induced MMP-9 activity (P < 0.05; n = 5) as measured by gelatin zymography. Conclusively, estradiol abolished Ox-LDL-stimulated increase in the levels of macrophage-derived MMP-9 protein and activity in human Mφ. This effect was reversed by TAM but not by PROG. These data suggest that at least part of the protective effect of estrogen occurs by attenuation of Ox-LDL alterations in MMP-9 expression.
authors.affiliation: Cardiometabolic Research Unit, Division of Endocrinology, Metabolism and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA. huzui@u-fukui.ac.jp
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Uzui
authors.forename: Satyesh K
authors.initials: SK
authors.lastname: Sinha
authors.forename: Tripathi B
authors.initials: TB
authors.lastname: Rajavashisth
mesh_terms: D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology; D058226:Plaque, Atherosclerotic / Q000378:metabolism; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
chemical_list: D008077:Lipoproteins, LDL; D019714:Tissue Inhibitor of Metalloproteinases; C099252:oxidized low density lipoprotein; D004958:Estradiol; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9