Abstract 339: EMMPRIN is Expressed on Progenitor Cell-Derived Foam Cells and Regulates MT1-MMP and MMP-9
Foam cell-derived matrix metalloproteinases (MMPs) such as MMP-9 and MT1-MMP are thought to induce plaque rupture in atherosclerosis. However, the key mechanism of MMP regulation within the plaque has not been clarified, yet. We could recently identify the Extracellular MatrixMetalloProteinase Inducer “EMMPRIN” as an important modulator of MMP activity in cardiovascular cells such as monocytes and smooth muscle cells (Circulation 2006). To our knowledge, EMMPRIN has not been characterized on CD34-positive progenitor cells or foam cells, yet. Therefore, by using a novel model of foam cell formation from CD34-positive cells, we have studied EMMPRIN expression during foam cell differentiation and its functional relevance. Methods and Results: Human CD34+-progenitor cells were freshly derived from umbilical veins and were coincubated with platelets (2x108/ml) for 12 days resulting in large, lipid-loaden CD68 positive foam cells as confirmed by immunocytochemistry, flow cytometry and confocal and electron microscopy. While CD34+-cells did not express EMMPRIN or MT1-MMP, foam cells strongly expressed EMMPRIN on the cell surface [flow cytometry, immunocytochemistry]. In fact, EMMPRIN expression was associated with MT1-MMP expression [flow cytometry] and with enhanced MMP-9 secretion into the cell culture supernatant [SDS-Page gelatin zymography]. Effective gene silencing of EMMPRIN by small interfering RNA (siRNA) significantly reduced the expression of MT1-MMP and of MMP-9 indicating functional relevance of EMMPRIN in foam cells. Control-siRNA had no effect on both MT1-MMP and MMP-9. Notably, MMP-2 was not affected by EMMPRIN gene silencing. Conclusion: CD34+-progenitor cells differentiate into foam cells upon coincubation with platelets. EMMPRIN is expressed on mature foam cells (but not on CD34+-progenitor cells), effectively modulates MMP activity, and, thus represents a promising target to prevent plaque rupture.