(Circulation. 1999;99:993-998.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Oxidized Low-Density Lipoprotein Regulates Matrix Metalloproteinase-9 and Its Tissue Inhibitor in Human Monocyte-Derived Macrophages
From the Atherosclerosis Research Center, Division of Cardiology, and the Burns and Allen Research Institute, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, Calif.
Correspondence to Prediman K. Shah, MD, Division of Cardiology, Room 5347, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048-0750. E-mail ShahP{at}cshs.org
Background—Macrophages in human atherosclerotic plaques produce a family of matrix metalloproteinases (MMPs), which may influence vascular remodeling and plaque disruption. Because oxidized LDL (ox-LDL) is implicated in many proatherogenic events, we hypothesized that ox-LDL would regulate expression of MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) in monocyte-derived macrophages.
Methods and Results—Mononuclear cells were isolated from normal
human subjects with Ficoll-Paque density gradient
centrifugation, and adherent cells were allowed to
differentiate into macrophages during 7 days of culture in
plastic dishes. On day 7, by use of serum-free medium, the
macrophages were incubated with various concentrations of
native LDL (n-LDL) and copper-oxidized LDL. Exposure to ox-LDL (10 to
50 µg/mL) increased MMP-9 mRNA expression as analyzed by
Northern blot, protein expression as measured by ELISA and Western
blot, and gelatinolytic activity as determined by
zymography. The increase in MMP-9 expression was associated with
increased nuclear binding of transcription factor NF-
B and AP-1
complex on electromobility shift assay. In contrast, ox-LDL (10 to 50
µg/mL) decreased TIMP-1 expression. Ox-LDL–induced increase in MMP-9
expression was abrogated by HDL (100 µg/mL). n-LDL had no
significant effect on MMP-9 or TIMP-1 expression.
Conclusions—These data demonstrate that unlike n-LDL, ox-LDL upregulates MMP-9 expression while reducing TIMP-1 expression in monocyte-derived macrophages. Furthermore, HDL abrogates ox-LDL–induced MMP-9 expression. Thus, ox-LDL may contribute to macrophage-mediated matrix breakdown in the atherosclerotic plaques, thereby predisposing them to plaque disruption and/or vascular remodeling.
Key Words: lipoproteins • metalloproteinases • atherosclerosis
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|
|
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|
|
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|
|
|
|
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|
|
|
|
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|
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|
|
|
|
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|
|
|
|
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|
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