SUMMARY 1. The present study compares plasma urokinase plasmino- gen activator (uPA) peptide levels, plasma plasminogen inhibitor (PAI-1) activity and urokinase receptors (uPAR) on peripheral blood monocytes of patients with stable coronary artery disease (SCAD) and healthy volunteers. 2. Urokinase plasminogen activator levels were analysed by ELISA and PAI-1 activity was determined by a plasmin gener- ation method using the chromogenic substrate S2390. Relative uPAR numbers and the adhesion molecules CD11b/CD18 on peripheral blood monocytes were estimated using specific antibodies and flow cytometry. 3. Patients with SCAD were found to have higher plasma uPA peptide levels than age-matched healthy subjects (10.400.99 vs 8.250.53 pmol/L, respectively; P < 0.05). 4. Plasma PAI-1 activity was also higher in patients with SCAD than in healthy subjects (13.62.5 vs 5.21.0 IU/mL, respectively; P < 0.05). 5. Relative uPAR and CD11b/CD18 adhesion molecules were similar on peripheral blood monocytes of patients with SCAD and in healthy subjects. 6. The data indicate a pattern of expression/activity of uPA and PAI-1 in patients with SCAD suggestive of an impaired fibrinolytic ability. Key words: coronary artery disease, monocyte, plasminogen activator inhibitor, urokinase, urokinase receptors. INTRODUCTION Ischaemic heart disease is frequently coupled with coronary athero- sclerosis and the rupture of atherosclerotic plaques with super- imposed thrombosis is a major cause for acute events in coronary artery disease. 1 The development of ischaemic heart disease is accompanied by a reduced fibrinolytic capacity. 2,3 Reduced fibri- nolysis may also be involved in the progression of atherosclerosis. 4–6 Fibrinolytic capacity relates to the function of the plasminogen acti- vator (PA) system. There are two types of PA, tissue plasminogen activator (tPA), which functions, in general, in circulating blood, and plasminogen activator of the urokinase type (uPA), which potentiates pericellular fibrinolysis. The PA system converts plasminogen to plasmin, the latter not only affects the rate of fibrin degradation but can also activate metalloproteinases and latent forms of cytokines, such as transforming growth factor (TGF)-, and even release basic fibroblast growth factor-2 from the extracellular matrix, two factors implicated in atherogenesis. 7,8 Fibrinolysis can also be regulated by the plasminogen activator inhibitor-1 (PAI-1), the major physio- logical inhibitor of both tPA and, in humans, uPA. 9 Urokinase plasminogen activator is a complex protein consisting of multiple domains and includes a serine protease site located within the C-terminal catalytic domain and an epidermal growth factor (EGF)- like domain within its N-terminal region. 10 Its serine protease can actively participate in fibrinolysis as well as tissue remodelling, angiogenesis, tumour growth and even metastasis. It has been suggested that its EGF-like domain may be responsible for its mitogenic and chemotactic properties. 11 Endothelial, vascular smooth muscle cells and blood monocytes/ macrophages produce uPA and uPA receptors (uPAR); 12–15 in the latter cell type, uPAand uPAR production can be greatly increased during exposure to the inflammatory cytokines tumour necrosis factor (TNF)- and interferon (IFN)-. 14 Under these circumstances, when uPA binds to its cell surface receptor (uPAR), its proteolytic activity increases greatly. 16 This complex is critical for monocyte chemotaxis 17 and, during cell migration, the receptor–uPA complex is localized at its leading cell edge, participating in the degradation of extracellular matrix. 16,17 Monocytes are also recognized to play an important role in thrombus formation, initiated by local increases in tissue factor expression. 18 In this instance, their ability to produce uPAand uPAR suggests that they have a potential to regulate proteo- lysis within thrombi. Thus, it is possible that, depending on local environmental conditions, monocytes exert either procoagulative or fibrinolytic effects. In atherosclerotic lesions within coronary arteries, monocytes also participate in lipid and cell debris removal as well as regulating inflammation. 3,5 Here, their initial adhesion to endothelium and migration into the vessel wall is associated with the expression of the 2-integrins CD11b/CD18; 19 this complex (Mac-1) plays a pivotal role in monocyte adhesion to damaged endothelium. 20,21 The aim of the present study was to determine the extent to which expression of the uPA/PAI-1/uPAR system may be up-regulated in patients with stable coronary artery disease (SCAD). To this end, we compared plasma uPA peptide levels, plasma PAI-1 functional activity and monocyte surface uPAR and CD11b/CD18 expression in patients with SCAD and healthy subjects. Our results demonstrate that, compared with healthy subjects, patients with SCAD exhibit UROKINASE PLASMINOGEN ACTIVATOR SYSTEM IN HUMANS WITH STABLE CORONARY ARTERY DISEASE TL Krasnikova,* YeV Parfyonova,* IAAlekseeva,* TI Arefieva,* SA Mukhina,* AB Dobrovolsky,* YeV Titaeva,* AA Lyakishev,* TJ Resink, † P Erne ‡ and VA Tkachuk* *Cardiology Research Centre of Ministry of Health, Moscow, Russia, † Department of Resåarch, Basel University Hospital, Basel and ‡ Division of Cardiology, Kantonsspital Luzern, Luzern, Switzerland Correspondence: Professor VA Tkachuk, Cardiology Research Centre of Ministry of Health, 3rd Cherepkovskaya Street 15a, Moscow 121552, Russian Federation. Email: <tkachuk@cardio.med.msu.su.> Received 20 August 1998; revision 25 November 1998; accepted 30 November 1998. Clinical and Experimental Pharmacology and Physiology (1999) 26, 354–357