Regulation, Location and Activity of Plasminogen Activator Inhibitor 2 (PAI-2) in Peripheral Blood Monocytes, Macrophages and Foam Cells

Summary

Monocytes, macrophages and foam cells are central to atherogenesis. We have examined the potential ability of monocytes, macrophages and foam cells to affect the stability of deposited fibrin, characteristic of the atherosclerotic plaque, by their production of plasminogen activators and their inhibitors. Monocytes respond to thrombin and LPS by up-regulation of PAI-2 synthesis, and PAI-2 is their major product among the plasminogen activators/inhibitors. In contrast, macrophages and foam cells, while they did produce PAI-2, did not respond to thrombin and LPS by an increase in its synthesis. All PAI-2 produced by macrophages and foam cells was accumulated intracellularly, whereas monocytes also secreted PAI-2. Secreted PAI-2 was active as an inhibitor of u-PA, whereas intracellular PAI-2 required detergent treatment to generate activity. Thus monocytes, but not macrophages or foam cells, produce and secrete active PAI-2, thus potentially affecting fibrin stability in the local environment.

• References

• 1 Ross R. The pathogenesis of atherosclerosis. N Engl J Med 1986; 314: 488-499
• 2 Rajavashisth TB, Andalibi A, Territo MC, Berliner JA, Navab M, Fogelman AM, Lusis AJ. Induction of endothelial cell expression of granulocyte and macrophage colony stimulating factors by modified low-density lipoproteins. Nature 1990; 344: 254-257
• 3 Goldstein JL, Ho YK, Basu SK, Brown MS. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci USA 1979; 76: 333-337
• 4 Collen D, Juhan-Vague I. Fibrinolysis and atherosclerosis. Sem Thromb Haemost 1988; 14: 180-183
• 5 Rapaport SI, Rao LVM. Initiation and regulation of tissue factor-dependent blood coagulation. Arterioscler Thromb 1994; 14: 1111-1121
• 6 Wilcox JN, Smith KM, Schwartz SM, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA 1989; 86: 2839-2843
• 7 Saksela O, Hovi T, Vaheri A. Urokinase-type plasminogen activator and its inhibitor secreted by cultured human monocytes-macrophages. J Cell Physiol 1985; 122: 125-132
• 8 Hart PH, Vitti GF, Burgess DR, Singleton DK, Hamilton JA. Human monocytes can produce tissue-type plasminogen activator. J Exp Med 1989; 169: 1509-1515
• 9 Castellote JC, Grau E, Linde MA, Pujol-Moix N, Rutllant MLI. Detection of both type 1 and type 2 plasminogen activator inhibitors in human monocytes. Thromb Haemost 1990; 63: 67-71
• 10 Schwartz BS, Monroe MC, Levin EG. Increased release of plasminogen activator inhibitor type 2 accompanies mononuclear cell tissue factor response to lipopolysaccharide. Blood 1988; 71: 734-734L
• 11 Schwartz BS, Bradshaw JD. Differential regulation of tissue factor and plasminogen activator inhibitor by human mononuclear cells. Blood 1989; 74: 1644-1650
• 12 Genton C, Kruithof EKO, Schleuning W-D. Phorbol ester induces the biosynthesis of glycosylated and nonglycosylated plasminogen activator inhibitor 2 in high excess over urokinase-type plasminogen activator in human U937 lymphoma cells. J Cell Biol 1987; 104: 705-712
• 13 Morgenstem KA, Henzel WJ, Baker JB, Wong S, Pastuszyn A, Kisiel W. Isolation and characterization of an intracellular serine proteinase inhibitor from a monkey kidney epithelial cell line. J Biol Chem 1993; 268: 21560-21568
• 14 Coughlin P, Sun J, Cerruti L, Salem HH, Bird P. Cloning and molecular characterization of an intracellular serine proteinase inhibitor. Proc Natl AcadSci USA 1993; 90: 9417-9421
• 15 Kumar S, Baglioni C. Protection from tumor necrosis factor-mediated cytolysis by overexpression of plasminogen activator inhibitor type-2. J Biol Chem 1991; 266: 20960-20964
• 16 Dickinson JL, Bates EJ, Ferrante A, Antalis TM. Plasminogen activator inhibitor type 2 inhibits tumor necrosis factor α-induced apoptosis. J Biol Chem 1995; 270: 27894-27904
• 17 Kruithof EKO, Baker MS, Bunn CL. Biological and clinical aspects of plasminogen activator inhibitor type 2. Blood 1995; 86: 4007-4024
• 18 Ritchie HM, Jamieson A, Booth NA. Peripheral blood monocyte synthesis of plasminogen activator inhibitor 2 in response to native and modified LDL. Thromb Haemost 1995; 74: 1521-1527
• 19 Ritchie HM, Jamieson A, Booth NA. Thrombin modulates synthesis of plasminogen activator inhibitor type 2 by human peripheral blood monocytes. Blood 1995; 86: 3428-3435
• 20 Noble RP. Electrophoretic separation of plasma lipoproteins in agarose gel. J Lipid Research 1968; 09: 693-700
• 21 Bradford MM. A rapid and sensitive method for the quantification of microgram quantities of protein utilising the principles of protein-dye binding. Anal Biochem 1976; 72: 248-254
• 22 Rouis M, Nigon F, Lafuma C, Hornebeck W, Chapman MJ. Expression of elastase activity by human monocyte-macrophages is modulated by cellular cholesterol content, inflammatory mediators and phorbol myristate acetate. Arterioscler 1990; 10: 246-255
• 23 Funk JL, Feingold KR, Moser AH, Grun feld. Lipopolysaccharide stimulation of RAW 264.7 macrophages induces lipid accumulation and foam cell formation. Atheroscler 1993; 98: 67-82
• 24 MacGregor IR, Booth NA. An enzyme-linked immunosorbent assay used to study the cellular secretion of endothelial plasminogen activator inhibitor (PAI-1). Thromb Haemost 1988; 59: 68-72
• 25 MacGregor IR, MacDonald S, Dawes J, Micklem LR, James K. A monoclonal antibody enzyme linked immunosorbent assay directed towards a fibrin-binding region of tissue-type plasminogen activator. Fibrinolysis 1987; 01: 247-252
• 26 Reith A, Bennett B, Booth NA. Plasminogen activator inhibitor (PAI-2) in pregnancy plasma and ovarian cysts, studied by zymography after nondenaturing gel electrophoresis. Fibrinolysis 1989; 03: 159-163
• 27 Sancho ES, Tonge DW, Hockney RC, Booth NA. Purification and characterization of active and stable recombinant plasminogen activator inhibitor accumulated at high levels in Escherichia coli . Eur J Biochem 1994; 224: 125-131
• 28 Booth NA, Anderson JA, Bennett B. Plasminogen activators in alcoholic cirrhosis:demonstration of increased tissue type and urokinase type activators. J Clin Path 1984; 37: 772-777
• 29 Robbie LA, Booth NA, Brown PAJ, Bennett B. Inhibitors of fibrinolysis are elevated in the atherosclerotic plaque. Arterioscler Thromb Vase Biol 1996; 16: 539-545
• 30 Raetz CRH, Ulevitch RJ, Wright SD, Sibley CH, Ding A, Nathan CF. Gram-negative endotoxin:an extraordinary lipid with profound effects on eukaryotic signal transduction. FASEB J 1991; 05: 2652-2660
• 31 Jungi TW, Miserez R, Brcic M, Pfi ster. Change in sensitivity to lipopolysaccharide during the differentiation of human monocytes to macrophages in vitro. Experientia 1994; 50: 110-114
• 32 Scheibenbogen C, Moser H, Krause S, Andreesen R. Interferon-gamma-induced expression of tissue factor activity during human monocyte to macrophage maturation. Haemost 1992; 22: 173-178
• 33 Lesnik P, Rouis M, Skarlatos S, Kruth HS, Chapman MJ. Uptake of exogenous free cholesterol induces up-regulation of tissue factor expression in human monocyte-derived macrophages. Proc Natl Acad Sci USA 1992; 89: 10370-10376
• 34 Rosenfeld ME, Khoo JC, Miller E, Parthasarathy S, Palinski W, Witztum JL. Macrophage-derived foam cells freshly isolated from rabbit atherosclerotic lesions degrade modified lipoproteins, promote oxidation of low-density lipoproteins and contain oxidation-specific lipid-protein adducts. J Clin Invest 1991; 87: 90-99
• 35 Tipping PG, Davenport P, Gallicchio M, Filonzi EL, Apostolopoulos J, Wojta J. Atheromatous plaque macrophages produce plasminogen activator inhibitor type-1 and stimulated its production by endothelial cells and vascular smooth muscle cells. Am J Pathol 1993; 143: 875-885
• 36 Gan H, Newman GW, Remold HG. Plasminogen activator inhibitor type 2 prevents programmed cell death of human macrophages infected with Mycobacterium avium, Serovar 4. J Immunol 1995; 155: 1304-1315
• 37 Wun T-C, Reich E. An inhibitor of plasminogen activator from human placenta. Purification and characterization. J Biol Chem 1987; 262: 3646-3652
• 38 Jensen PH, Nykjaer A, Andreasen A, Lund LR, Astedt B, Lecander I, Gliemann J. Urokinase binds to a plasminogen activator inhibitor type-2-like molecule in placental microvillus membranes. Biochim Biophys Acta 1989; 986: 135-140
• 39 Jensen PH, Lorand L, Ebbesen P, Gliemann J. Type-2 plasminogen activator inhibitor is a substrate for trophoblast transglutaminase and factor XIIIa-transglutaminase-catalyzed cross linking to cellular and extracellular structures. Eur J Biochem 1992; 214: 141-147
• 40 Aeschlimann D, Paulsson M. Transglutaminases:protein cross-linking enzymes in tissues and body fluids. Thromb Haemost 1994; 71: 402-412
• 41 Mikus P, Urano T, Liljestrom P, Ny T. Plasminogen activator inhibitor 2 (PAI-2) is a spontaneously polymerising serpin. Eur J Biochem 1993; 213: 1071-1076
• 42 Reid VC, Mitchison MJ. Toxicity of oxidised low density lipoprotein towards mouse peritoneal macrophages in vitro. Atheroscler 1993; 98: 17-24