Increased expression of u-PA and u-PAR on monocytes by LDL and Lp(a) lipoproteins - Consequences for plasmin generation and monocyte adhesion

Monocyte-derived foam cells figure prominently in rupture-prone regions of atherosclerotic plaque. As urokinase/urokinase-receptor (u-PA/u-PAR) is the trigger of a proteolytic cascade responsible for ECM degradation, we have examined the effect of atherogenic lipoproteins on monocyte surface express ion of u-PAR and u-PA. Peripheral blood monocytes, isolated from 10 healthy volunteers, were incubated with 10 to 200 mu g/ml of native or oxidised (o x-) atherogenous lipoproteins for 18 h and cell surface expression of u-PA and u-PAR was analysed by flow cytometry. Both LDL and Lp(a) induced a dose -dependent increase in u-PA (1.6-fold increase with 200 mu g/ml of ox-LDL) and u-PAR [1.7-fold increase with 200 mu g/ml of ox-Lp(a)]. There is a grea t variability of the response among the donors, some of them remaining non- responders (absence of increase of u-PA or u-PAR) even at 200 mu g/ml of li poproteins. In positive responders, enhanced u-PA/u-PAR is associated with a significant increase of plasmin generation (1.9-fold increase with 200 mu g/ml of ox-LDL), as determined by an amidolytic assay. Furthermore, monocy te adhesion to vitronectin and fibrinogen was significantly enhanced by the lipoproteins [respectively 2-fold and 1.7-fold increase with 200 mu g/ml o f ox-Lp(a)], due to the increase of u-PAR and ICAM-1 which are receptors fo r vitronectin and fibrinogen. These data suggest that atherogenous lipoprot eins could contribute to the development of atheromatous plaque by increasi ng monocyte adhesion and trigger plaque weakening by inducing ECM degradati on.