Oxidized low-density lipoproteins stimulate extracellular matrix metalloproteinase Inducer (EMMPRIN) release by
Cornelia Haug1, Christina Lenz, Fredy Díaz
1Central Department Clinical Chemistry, University Hospital Ulm, Robert-Koch-Strasse 8, D-89070 Ulm, Germany. cornelia.haug@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.
Conclusions:
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.
Insights
Oxidized LDLs increase soluble EMMPRIN release from smooth muscle cells, promoting matrix degradation. This suggests a cycle where oxidized LDLs drive matrix metalloproteinase (MMP) release and activity in atherosclerosis.
Area of Science:
- Cardiovascular Biology
- Cellular Biochemistry
Background:
- Matrix metalloproteinases (MMPs) are implicated in atherogenesis.
- Extracellular MMP inducer (EMMPRIN) stimulates MMP synthesis and is found in human atheroma.
Purpose of the Study:
- To investigate the effect of oxidized low-density lipoproteins (oxLDLs) on EMMPRIN expression in human coronary artery smooth muscle cells (HCA-SMCs).
Main Methods:
- HCA-SMCs were treated with oxLDLs.
- EMMPRIN release and cell-associated levels were measured.
- Western blot analysis was used to assess MMP-1 and MMP-2.
- Effects of antioxidants, EDTA, and GM6001 were evaluated.
Main Results:
- OxLDLs significantly increased EMMPRIN release into supernatants and decreased cell-associated EMMPRIN.
- Antioxidants, EDTA, and GM6001 antagonized these oxLDL effects.
- MMP-1 and MMP-2 induced shedding of EMMPRIN, and oxLDL upregulated MMP-1 and MMP-2 synthesis.
- Soluble EMMPRIN from macrophages also increased MMP-1 and MMP-2 synthesis in HCA-SMCs.
Conclusions:
- OxLDLs stimulate soluble EMMPRIN release via MMP-dependent shedding.
- This process may create a feedback loop, as soluble EMMPRIN enhances MMP synthesis, contributing to matrix degradation in atherosclerosis.
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