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

Abstract

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. Key Words: smooth muscle cells Ⅲ low density lipoproteins Ⅲ matrix metalloproteinases Ⅲ extracellular MMP inducer Ⅲ atherosclerosis D eposition of low-density lipoproteins (LDLs) in the vessel wall and their oxidative modification seem to initiate, or at least accelerate, the atherosclerotic process by several mechanisms, including promotion of foam cell formation, chemotactic effects on monocytes, and mitogenic effects on smooth muscle cells. Recent studies have demonstrated that oxidized LDLs (oxLDLs) increase the expression of matrix metalloproteinases (MMPs) in endothelial cells, monocyte-derived macrophages, and smooth muscle cells [1][2][3] and that MMP expression is enhanced in atherosclerotic plaque tissue. 4 MMPs increase smooth muscle cell migration and proliferation 5,6 and also seem to promote plaque instability by inducing extracellular matrix degradation. 7 Expression of extracellular MMP inducer (EMMPRIN) in human atheroma has been described recently. 8,9 EMMPRIN, also called CD147 or basigin, is a highly glycosylated plasma membrane protein (Ϸ58 kDa) belonging to the immunoglobulin superfamily. EMMPRIN is expressed on several cell types like leukocytes and different tumor cells 10 and stimulates MMP production in fibroblasts and various tumor cells. 11,12 Several studies have shown that cancer cells express significantly higher EMMPRIN levels than normal cells, and it has been proposed that elevated EMMPRIN expression in tumor cells may promote tumor progression by inducing MMP expression in peritumoral stromal cells. In this study, we have demonstrated that EMMPRIN is expressed in cultured human coronary artery smooth muscle cells (HCA-SMCs) and that oxLDL significantly enhanced the release of soluble EMMPRIN as well as MMP-1 and MMP-2 release. In addition, we have shown that MMP-1 and MMP-2 seem to promote the cleavage of soluble EMMPRIN from the cell surface and that soluble EMMPRIN stimulates MMP synthesis in HCA-SMC. Thus our data suggest that oxLDL might induce a circular upregulation of matrix degradation. Conclusion-Our Materials and...

Plasma Cyclophilin A Is a Novel Biomarker for Coronary Artery Disease

“…EMMPRIN, a putative CyPA receptor, has been identified as a tumor cell membrane protein that is expressed in VSMC, is activated by ROS and stimulates matrix metalloproteinase production. 34 A recent study demonstrated ROS-dependent increases in EMMPRIN, 35 which may be activated by the binding of extracellular CyPA. 36 Therefore, ROS-induced secretion of CyPA may also contribute to the development of unstable atherosclerotic plaque and plaque rupture.…”

CD147 immunoglobulin superfamily receptor function and role in pathology

“…Increased MMP expression was obtained following the exogenous treatment of fibroblasts with recombinant CD147 protein as well as the adenoviral transduction of fibroblasts with CD147 in the absence of tumor cells (Li et al 2001) These studies indicated that membrane bound and soluble CD147 are equally capable of inducing MMP production from fibroblast cells. The soluble form of CD147 has been detected in conditioned media as full length protein (Taylor et al 2002) or as part of shed microvesicles (Sidhu et al 2004), as well as in forms lacking the transmembrane and cytoplasmic domain derived from MMP mediated cleavage of CD147 from the cell surface (Haug et al 2004;Egawa et al 2006;Maatta et al 2006). …”

Suppression of oxLDL‐Induced MMP‐9 and EMMPRIN Expression by Berberine via Inhibition of NF‐κB Activation in Human THP‐1 Macrophages

“…Increasing evidence shows that in response to certain proatherogenic stimuli such as oxLDL, EMMPRIN is upregulated strongly in atherosclerosis-related cells, including macrophages and coronary smooth muscle cells (Major et al, 2002;Haug et al, 2004;Schmidt et al, 2006). It also increases in activated platelets and mediated NF-jB activation by inducing the production of MMP-9, IL-6, and TNF-a (Schmidt et al, 2008).…”