on August 19, 2004
Published online before print August 19, 2004, doi: 10.1161/01.ATV.0000142806.59283.11
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Submitted on May 8, 2004
Accepted on August 2, 2004
Oxidized Low-Density Lipoproteins Stimulate Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) Release by Coronary Smooth Muscle Cells
Cornelia Haug *;
From the Central Department of Clinical Chemistry (C.H., C.L., F.D., M.G.B.), University Hospital Ulm, Germany; and the Laboratory of Molecular Biology (F.D.), Faculty of Medicine, Catholic University of Smma. Concepción, Chile.
* To whom correspondence should be addressed. E-mail: cornelia.haug{at}medizin.uni-ulm.de.
Objective--Matrix metalloproteinases (MMPs) seem to play a prominent role in atherogenesis. Extracellular MMP inducer (EMMPRIN), a cell surface glycoprotein which stimulates MMP synthesis, has recently been detected in human atheroma. We have investigated the influence of oxidized low-density lipoproteins (oxLDLs) on EMMPRIN expression in human coronary artery smooth muscle cells (HCA-SMCs).
Methods and Results--OxLDL induced a significant increase of EMMPRIN release into HCA-SMC supernatants and a concomitant decrease of cell-associated EMMPRIN. These effects were antagonized by antioxidants as well as by EDTA and the MMP inhibitor GM6001. Western blot analysis demonstrated that MMP-1 and MMP-2 induce the cleavage of the extracellular domain from cell-associated EMMPRIN. MMP-1 and MMP-2 synthesis was upregulated by oxLDL, and, in addition, we have shown that soluble EMMPRIN, isolated from macrophage supernatants, increased MMP-1 and MMP-2 synthesis in HCA-SMC.
Conclusion--Our data suggest that oxLDLs stimulate the release of soluble EMMPRIN, at least in part, by MMP-dependent shedding from the cell surface. Additionally, oxLDLs might induce a circular upregulation of matrix degradation because, in turn, soluble EMMPRIN stimulates MMP synthesis in HCA-SMC.
Key words: smooth muscle cells • low density lipoproteins • matrix metalloproteinases • extracellular MMP inducer • atherosclerosis
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