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17β-Estradiol Inhibits Oxidized Low-Density Lipoprotein-Induced Increase in Matrix Metalloproteinase-9 Expression in Human Macrophages
  1. Hiroyasu Uzui, MD, PhD*,
  2. Satyesh K. Sinha, PhD*,
  3. Tripathi B. Rajavashisth, PhD*†
  1. From the *Cardiometabolic Research Unit, Division of Endocrinology, Metabolism and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles and David Geffen School of Medicine at University of California Los Angeles, Los Angeles; and †Omics Biotechnology, Inc, Lawndale, CA.
  1. Received November 13, 2010, and in revised form April 23, 2011.
  2. Accepted for publication April 27, 2011.
  3. Reprints: Tripathi B. Rajavashisth, PhD, Cardiometabolic Research Unit, Division of Endocrinology, Metabolism and Molecular Medicine, Charles R. Drew University and David Geffen School of Medicine at UCLA, 1731 East 120th St, Los Angeles, CA. E-mail: tripathirajavashisth{at}cdrewu.edu; rajavashisth{at}ucla.edu.
  4. Present address of Dr. Hiroyasu Uzui: Division of Cardiovascular Medicine, University of Fukui Faculty of Medical Sciences, 23-3 Shimoaizuki, Eiheiji-cho, Fukui 910-1193, Japan; Phone: 0776-61-3111; E-mail: huzui{at}u-fukui.ac.jp.
  5. Supported by grants from the National Heart, Lung, and Blood Institute (HL51980 and HL58555) to Dr. Rajavashisth.

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.

Key Words
  • estrogen
  • lipoproteins
  • macrophages
  • metalloproteinases
  • tissue inhibitor of metalloproteinases

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