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(Circulation. 2005;111:2820-2827.)
© 2005 American Heart Association, Inc.

Vascular Medicine

Furin-Like Proprotein Convertases Are Central Regulators of the Membrane Type Matrix Metalloproteinase–Pro-Matrix Metalloproteinase-2 Proteolytic Cascade in Atherosclerosis

Philipp Stawowy, MD; Heike Meyborg, MSc; Dietger Stibenz, PhD; Núbia Borges Pereira Stawowy, DMD; Mattias Roser, MD; Usan Thanabalasingam, MD; John P. Veinot, MD; Michel Chrétien, MD; Nabil G. Seidah, PhD; Eckart Fleck, MD; Kristof Graf, MD

From the Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany (P.S., H.M., D.S., N.B.P.S., M.R., U.T., E.F., K.G.); Diseases of Aging and Regional Protein Chemistry Centers, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada (J.P.V., M.C.); and Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute, Montréal, Quebec, Canada (N.G.S.).

Correspondence to Dr Philipp Stawowy, Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany. E-mail stawowy{at}dhzb.de

Received August 25, 2004; revision received December 23, 2004; accepted January 19, 2005.

Background— Accumulation of macrophages and their in situ expression of matrix metalloproteinases (MMPs) are important determinants of plaque stability. Activation of membrane-bound MT1-MMP, the major activator of pro-MMP-2, requires intracellular endoproteolytic cleavage of its precursor protein. This type of activation typically requires suitable furin-like proprotein convertases (PCs), specifically furin and PC5. The present study was done to investigate the function of MT1-MMP as well as furin-like PCs in mononuclear inflammatory cells.

Methods and Results— Macrophage differentiation of human monocytic THP-1 cells was accompanied by increased expression of furin, PC5, and MT1-MMP. Some pro-MMP-2 activation was found in macrophages, but pro-MMP-2 level or activation was not enhanced after stimulation with the proinflammatory mediators tumor necrosis factor- or lipopolysaccharide. However, culturing of macrophages in conditioned medium from serum-starved vascular smooth muscle cells, which constitutively secrete pro-MMP-2, resulted in a strong pro-MMP-2 activation. Inhibition of furin-like PCs with the specific pharmacological inhibitor decanoyl-RVKR-chloromethylketone (dec-CMK) inhibited MT1-MMP activation in macrophages. Dec-CMK or furin-specific small interfering RNA significantly inhibited macrophage MT1-MMP–dependent activation of vascular smooth muscle cell–derived pro-MMP-2. Flow cytometry demonstrated that human circulating monocytes express furin and PC5, and MT1-MMP and immunohistochemistry revealed their colocalization in macrophages in advanced human atherosclerotic lesions.

Conclusions— Furin-like PCs (furin and PC5) play a central role in a MT-MMP–MMP-2 proteolytic cascade, involving provision of macrophage MT1-MMP for the activation of pro-MMP-2 synthesized by other cells. Furin and PC5 are expressed in human peripheral blood mononuclear cells and colocalize with MT1-MMP in macrophages in the atherosclerotic plaque, supporting the hypothesis that they are potential targets in atherosclerosis.

Key Words: metalloproteinases • atherosclerosis • inflammation • proprotein convertases

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