Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1444-1455
© 1995 American Heart Association, Inc.
Articles |
Plasminogen Activator Expression in Human Atherosclerotic Lesions
From the Thrombosis Research Institute (F.L., F.B., V.V.K.), London, UK, and the Division of Hematology, Department of Medicine (F.L., D.A.H., F.B., E.K.O.K.) and Cardiovascular Surgery Service (M.H.), University Hospital Center (CHUV), Lausanne, Switzerland.
Correspondence to Florea Lupu, Vascular Biology Laboratory, Thrombosis Research Institute, Emmanuel Kaye Bldg, Manresa Rd, Chelsea, London SW3 6LR, UK.
Abstract The plasminogen activator (PA) system may participate in the pathogenesis of atherosclerosis by modulating the turnover of intimal fibrin and extracellular matrix deposits and by contributing to intimal cell migration. We present an analysis of tissue-type PA (tPA) and urokinase-type PA (uPA) expression at three levels: mRNA by in situ hybridization, antigen by immunohistochemistry, and enzymatic activity by histoenzymology and zymography. For PA colocalization with cellular or matrix components, we used double immunofluorescence labeling in conjunction with confocal microscopy. In normal arteries, tPA antigen and mRNA were detected in endothelial cells and smooth muscle cells (SMCs). In atherosclerotic arteries, tPA antigen and mRNA were increased in intimal SMCs and in macrophage-derived foam cells of fibrofatty lesions. Part of the tPA was detected in the extracellular space and colocalized with fibrin deposits. uPA antigen and mRNA were detected in association with the intimal macrophages and SMCs. A particularly high uPA expression was noted on macrophages localized on the rims of the necrotic core. Moreover, using a novel histoenzymological assay as well as classic zymography, we revealed uPA-dependent lytic activity in the advanced lesions, whereas in normal arteries, only tPA-dependent activity was detected, mainly over the vasa vasorum. Also, strong tPA and uPA staining was detected in neomicrovessels of the plaques, suggesting that PAs may play a role in plaque angiogenesis. Our results suggest a local dynamic process of PA-dependent proteolysis in lesion areas that is associated with macrophages and SMCs. A better comprehension of these proteolytic mechanisms in advanced atherosclerotic plaques may provide the basis for therapeutic approaches for plaque stabilization.
Key Words: atherosclerosis • tissue-type plasminogen activator • urokinase-type plasminogen activator • smooth muscle cells • macrophages
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|
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|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
Q. Xiao, M. J. S. Danton, D. P. Witte, M. C. Kowala, M. T. Valentine, T. H. Bugge, and J. L. Degen Plasminogen deficiency accelerates vessel wall disease in mice predisposed to atherosclerosis PNAS, September 16, 1997; 94(19): 10335 - 10340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Kauhanen, V. Siren, O. Carpen, A. Vaheri, M. Lepantalo, and R. Lassila Plasminogen Activator Inhibitor-1 in Neointima of Vein Grafts : Its Role in Reduced Fibrinolytic Potential and Graft Failure Circulation, September 16, 1997; 96(6): 1783 - 1789. [Abstract] [Full Text]
|
|
|
|
|
|
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|
|
|
|
|
|
M. R Garvin, M. Labinaz, K. Pels, V. M Walley, H. F Mizgala, and E. R O'Brien Arterial expression of the plasminogen activator system early after cardiac transplantation Cardiovasc Res, August 1, 1997; 35(2): 241 - 249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. R. Lijnen and D. Collen Impaired Fibrinolysis and the Risk for Coronary Heart Disease Circulation, November 1, 1996; 94(9): 2052 - 2054. [Full Text]
|
|
|
|
|
|
W.-Y. Zhang, I. Ishii, and H. S. Kruth Plasmin-mediated Macrophage Reversal of Low Density Lipoprotein Aggregation J. Biol. Chem., October 13, 2000; 275(42): 33176 - 33183. [Abstract] [Full Text] [PDF]
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|
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