The receptor for urokinase plasminogen activator is present in plasma from healthy donors and elevated in patients with paroxysmal nocturnal haemoglobinuria

Abstract

The urokinase plasminogen activator (uPA) is a proteolytic enzyme which converts the proenzyme plasminogen to the active serine protease plasmin. A cell surface receptor for uPA (uPAR) is attached to the cell membrane by a glycosyl-phosphatidylinositol anchor. Binding of uPA to uPAR leads to an enhanced plasmin formation and thereby an amplification of pericellular proteolysis. We have shown previously that uPAR is expressed on normal blood monocytes and granulocytes, but is deficient on affected blood monocytes and granulocytes in patients with paroxysmal nocturnal haemoglobinuria (PNH), and that uPAR is present in plasma from these patients. In this study a newly established sensitive enzyme-linked immunosorbent assay (ELISA) has been applied for quantitation of uPAR in plasma. Unexpectedly, we found that uPAR is not only present in PNH plasma but also in plasma from healthy individuals. In 39 healthy individuals the mean plasma-uPAR value +/- SD was 31 +/- 15 pM, median 28 (range 11-108), and the corresponding value for six PNH patients was 116 +/- 67 pM, median 90 (range 61-228). The elevated uPAR-level in PNH patients was highly significant (Mann-Whitney test; P < 0.0001), and may possibly contribute to the propensity for thrombosis in PNH by inhibition of the fibrinolytic system. Binding of pro-uPA by uPAR in plasma may interfere with the appropriate binding of pro-uPA to cell-bound uPAR and therefore inhibit cell-associated plasmin generation and fibrinolysis. It is likely that the uPAR in normal plasma reflects the overall level of activity of the uPAR-mediated cell surface proteolysis. The present ELISA may be used for studies of uPAR levels in plasma from patients with conditions in which this activity might be increased, such as cancer and inflammatory disorders. Future studies will determine if uPAR in plasma is a parameter of clinical importance in these diseases.

Soluble urokinase plasminogen activator receptor (suPAR) in the assessment of inflammatory activity of rheumatoid arthritis patients in remission

“…suPAR is derived from the cleavage and release of the membrane-bound protein, urokinasetype plasminogen activator receptor (uPAR), expressed by various immune cells, trophoblasts, endothelial cells, smooth muscle cells, and by certain tumor cells [1,2] . suPAR is detectable in low, but constant concentrations in plasma of healthy individuals [3,4] . However, activation of the immune system and the development of an inflammatory response lead to elevated plasma suPAR concentrations.…”

Proteinase 3 expression on the neutrophils of patients with paroxysmal nocturnal hemoglobinuria

“…serves a role as a NO effective scavenger in combination with NO, and NO is depleted, resulting in platelet aggregation and activation (24,25). Another factor associated with thrombosis is urokinase-type plasminogen activator receptor (uPAR), a GPI-linked protein expressed on neutrophils that mediates endogenous thrombolysis through a urokinase-dependent mechanism (26)(27)(28). Sloand et al (29) demonstrated that in patients with PNH, membrane GPI-anchored uPAR is decreased or absent on granulocytes and platelets, while soluble uPAR (suPAR) levels are increased in patients' plasma.…”

Evidence that the inhibition of cartilage proteoglycan breakdown by mannosamine is not mediated via inhibition of glycosylphosphatidylinositol anchor formation

“…The uPAR is anchored to the cell membrane via a GPI anchor [8], and the possibility existed that the inhibitory effect of mannosamine was mediated by a reduction in the amount of cell-bound uPAR and a concomitant increase in levels of uPAR in the culture medium, leading to a decrease in cell-associated plasminogen activation [9,10,31].…”