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Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1823-1829
Published online before print August 19, 2004, doi: 10.1161/01.ATV.0000142806.59283.11
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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1823.)
© 2004 American Heart Association, Inc.

Vascular Biology

Oxidized Low-Density Lipoproteins Stimulate Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) Release by Coronary Smooth Muscle Cells

Cornelia Haug; Christina Lenz; Fredy Díaz; Max G. Bachem

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 Santisima. Concepción, Chile.

Correspondence to Dr Cornelia Haug, Central Department Clinical Chemistry, University Hospital Ulm, Robert-Koch-Straße 8, D-89070 Ulm, Germany. 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.

This study demonstrates that oxidized low-density lipoproteins stimulate the release of soluble extracellular matrix metalloproteinase inducer (EMMPRIN) by human coronary artery smooth muscle cells, an effect which seems to result from enhanced EMMPRIN shedding. In addition, we have shown that isolated purified EMMPRIN stimulates MMP synthesis in coronary smooth muscle cells.


Key Words: smooth muscle cells • low density lipoproteins • matrix metalloproteinases • extracellular MMP inducer • atherosclerosis




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