O64	EMMPRIN regulates MMP activity in cardiovascular cells. Implications in Acute Myocardial Infarction.
1R.Schmidt, 2A.Bültmann, 2M.Ungerer, 1S.Fischel, 1N.Joghetaei, 1O.Bülbül, 3B.P.Toole, 1S.Thieme, 4A.E.May
1Deutsches Herzzentrum und 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, München, DE; 2ProCorde GmbH, Martinsried, DE; 3Dpt. Of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, South Carolina, US; 4Medizinische Klinik III, Eberhard-Karls Universität Tübingen, Tübingen, DE.

Objectives: Matrix Metalloproteinases (MMPs) are thought to promote atheroprogression and cardiovascular complications such as plaque rupture. The two cell surface receptors MT1-MMP (Membrane Type-1 MMP) and EMMPRIN (Extracellular Matrix Metalloproteinase Inducer) have been preferably found in unstable plaques. MT1-MMP binds and activates MMP-2, while, on tumor cells, EMMPRIN induces the synthesis of MMPs (including MT1-MMP and MMP-9) by yet unknown pathways. On cardiovascular cells, regulation of EMMPRIN in vivo or any functional relevance for MMP induction in vitro have not yet been described. Thus, we have studied EMMPRIN expression on monocytes in acute myocardial infarcton (MI) and its potential relevance for MMP activation. Methods and Results: In patients with acute MI [n=20], the surface expression of EMMPRIN and MT1-MMP [flow cytometry] was significantly enhanced on monocytes as well as MMP-9 activity [gelatin zymography] in the plasma as compared to patients with stable angina [n=20] or healthy volunteers [n=20]. At 6 months after successful revascularisation EMMPRIN, MT1-MMP and MMP-9 had returned to normal. In vitro, the secretion of MMP-9 by monocytes was induced by monocyte adhesion to immobilized recombinant EMMPRIN or to EMMPRIN-transfected Chinese Hamster Ovary cells. Furthermore, adherent EMMPRIN-transfected monocytic cells stimulated MMP-2 activity of human vascular smooth muscle cells (SMCs). Gene silencing of EMMPRIN by small interfering RNA hindered LPS-induced monocyte secretion of MMP-9 demonstrating a primary role of EMMPRIN in monocytic MMP-9 induction. Conclusions: EMMPRIN and MT1-MMP are upregulated on monocytes in acute myocardial infarction. During cellular interactions, EMMPRIN stimulates MMP-9 in monocytes and MMP-2 in SMCs. These data suggest that both MT1-MMP and EMMPRIN may present novel biomarkers of acute MI and are of functional relevance for MMP activation in acute MI.

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