Published online before print May 23, 2005, doi: 10.1161/CIRCULATIONAHA.104.502617
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(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
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
This article has been cited by other articles:
 |
|
 |
|
  K. Sugimoto, T. Ishibashi, T. Sawamura, N. Inoue, M. Kamioka, H. Uekita, H. Ohkawara, T. Sakamoto, N. Sakamoto, Y. Okamoto, et al. LOX-1-MT1-MMP axis is crucial for RhoA and Rac1 activation induced by oxidized low-density lipoprotein in endothelial cells Cardiovasc Res, October 1, 2009; 84(1): 127 - 136. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N Scamuffa, A Basak, C Lalou, A Wargnier, J Marcinkiewicz, G Siegfried, M Chretien, F Calvo, N G Seidah, and A-M Khatib Regulation of prohepcidin processing and activity by the subtilisin-like proprotein convertases Furin, PC5, PACE4 and PC7 Gut, November 1, 2008; 57(11): 1573 - 1582. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Yang, N. Lu, J. Zhou, Z.-n. Chen, and P. Zhu Cyclophilin A up-regulates MMP-9 expression and adhesion of monocytes/macrophages via CD147 signalling pathway in rheumatoid arthritis Rheumatology, September 1, 2008; 47(9): 1299 - 1310. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R.-N. Chen, Y.-H. Huang, Y.-C. Lin, C.-T. Yeh, Y. Liang, S.-L. Chen, and K.-H. Lin Thyroid Hormone Promotes Cell Invasion through Activation of Furin Expression in Human Hepatoma Cell Lines Endocrinology, August 1, 2008; 149(8): 3817 - 3831. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Lockwood, C. Oner, Y. H. Uz, U. A. Kayisli, S. J. Huang, L. F. Buchwalder, W. Murk, E. F. Funai, and F. Schatz Matrix Metalloproteinase 9 (MMP9) Expression in Preeclamptic Decidua and MMP9 Induction by Tumor Necrosis Factor Alpha and Interleukin 1 Beta in Human First Trimester Decidual Cells Biol Reprod, June 1, 2008; 78(6): 1064 - 1072. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Schneider, G. K. Sukhova, M. Aikawa, J. Canner, N. Gerdes, S.-M. T. Tang, G.-P. Shi, S. S. Apte, and P. Libby Matrix Metalloproteinase-14 Deficiency in Bone Marrow-Derived Cells Promotes Collagen Accumulation in Mouse Atherosclerotic Plaques Circulation, February 19, 2008; 117(7): 931 - 939. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Mitko, S. E Ulbrich, H. Wenigerkind, F. Sinowatz, H. Blum, E. Wolf, and S. Bauersachs Dynamic changes in messenger RNA profiles of bovine endometrium during the oestrous cycle Reproduction, February 1, 2008; 135(2): 225 - 240. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Mayer, J. Hamelin, M.-C. Asselin, A. Pasquato, E. Marcinkiewicz, M. Tang, S. Tabibzadeh, and N. G. Seidah The Regulated Cell Surface Zymogen Activation of the Proprotein Convertase PC5A Directs the Processing of Its Secretory Substrates J. Biol. Chem., January 25, 2008; 283(4): 2373 - 2384. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. G. Spinale Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function Physiol Rev, October 1, 2007; 87(4): 1285 - 1342. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. S. Spruill, A. S. Lowry, R. E. Stroud, C. E. Squires, I. M. Mains, E. C. Flack, C. Beck, J. S. Ikonomidis, A. J. Crumbley, P. J. McDermott, et al. Membrane-type-1 matrix metalloproteinase transcription and translation in myocardial fibroblasts from patients with normal left ventricular function and from patients with cardiomyopathy Am J Physiol Cell Physiol, October 1, 2007; 293(4): C1362 - C1373. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Fischoeder, H. Meyborg, D. Stibenz, E. Fleck, K. Graf, and P. Stawowy Insulin augments matrix metalloproteinase-9 expression in monocytes Cardiovasc Res, March 1, 2007; 73(4): 841 - 848. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Nagase, R. Visse, and G. Murphy Structure and function of matrix metalloproteinases and TIMPs Cardiovasc Res, February 15, 2006; 69(3): 562 - 573. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P.G. Sluijter, D. P.V. de Kleijn, and G. Pasterkamp Vascular remodeling and protease inhibition-bench to bedside Cardiovasc Res, February 15, 2006; 69(3): 595 - 603. [Abstract] [Full Text] [PDF]
|
|