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

Author

Ganné F, marc vasse, Jl, Beaudeux, Peynet J, François A, Paysant J, Lenormand B, Jp, Collet, Jp, Vannier, Soria J, and Soria C

Subjects
Lipoproteins, Fibrinogen, Macrophage-1 Antigen, Receptors, Cell Surface, Intercellular Adhesion Molecule-1, Urokinase-Type Plasminogen Activator, Monocytes, Receptors, Urokinase Plasminogen Activator, Lipoproteins, LDL, Cell Adhesion, Humans, Fibrinolysin, Vitronectin, Lipoprotein(a)
Abstract

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 expression of u-PAR and u-PA. Peripheral blood monocytes, isolated from 10 healthy volunteers, were incubated with 10 to 200 microg/ml of native or oxidised (ox-) 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 microg/ml of ox-LDL) and u-PAR [1.7-fold increase with 200 microg/ml of ox-Lp(a)]. There is a great 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 microg/ml of lipoproteins. In positive responders, enhanced u-PA/u-PAR is associated with a significant increase of plasmin generation ( .9-fold increase with 200 microg/ml of ox-LDL), as determined by an amidolytic assay. Furthermore, monocyte adhesion to vitronectin and fibrinogen was significantly enhanced by the lipoproteins [respectively 2-fold and 1.7-fold increase with 200 microg/ml of ox-Lp(a)], due to the increase of micro-PAR and ICAM-1, which are receptors for vitronectin and fibrinogen. These data suggest that atherogenous lipoproteins could contribute to the development of atheromatous plaque by increasing monocyte adhesion and trigger plaque weakening by inducing ECM degradation.

Published
1999

5. Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits the signaling pathways involved in the invasiveness and metastatic properties of highly invasive breast cancer cell lines: an in vitro study.

Author

Denoyelle, C, Vasse, M, Körner, M, Mishal, Z, Ganné, F, Vannier, J P, Soria, J, and Soria, C

Abstract

Cerivastatin is used in the treatment of hypercholesterolemia to inhibit 3-hydroxy 3-methylglutaryl coenzyme A reductase and thus prevent the synthesis of cholesterol precursors, such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), responsible, respectively, for translocation of Ras and Rho to the cell membrane, a step required for their cell signaling, leading to cell proliferation and migration. Recently, it has been suggested that non lipid-related effects of statins could play a beneficial role in cancer therapy. In this study, we have investigated the mechanisms by which statins inhibit cancer and the types of cancers which could benefit from this therapy. In MDA-MB-231 cells, an aggressive breast cancer cell line with spontaneous activation of Ras and NFkappaB and overexpression of RhoA, cerivastatin induced inhibition of both cell proliferation and invasion through Matrigel. This anti-proliferative effect was related to G(1)/S arrest due to an increase in p21(Waf1/Cip1). The anti-invasive effect was observed from 18 h and could be explained by RhoA delocalization from the cell membrane, resulting in disorganization of the actin fibers and disappearance of focal adhesion sites. The importance of RhoA inactivation in both these inhibitory effects was proved by their reversion by GGPP but not by FPP. Moreover, cerivastatin was also shown to induce inactivation of NFkappaB, in a RhoA inhibition-dependent manner, resulting in a decrease in urokinase and metalloproteinase-9 expression, two proteases involved in cell migration. The participation of Ras inactivation is considered a subsidiary mechanism for the effects of cerivastatin, as they were not rescued by FPP. Prolonged treatment of MDA-MB-231 cells with high doses of cerivastatin induced a loss of cell attachment. Interestingly, the effect of cerivastatin was considerably lower on poorly invasive MCF-7 cells. In conclusion, our results suggest that cerivastatin inhibits cell signaling pathways involved in the invasiveness and metastatic properties of highly invasive cancers.

Published
2001
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6. Activation of PAF receptor by oxidised LDL in human monocytes stimulates chemokine releases but not urokinase-type plasminogen activator expression.

Author

Beaudeux JL, Said T, Ninio E, Ganné F, Soria J, Delattre J, Soria C, Legrand A, and Peynet J

Subjects
Cells, Cultured, Chemokine CCL4, Copper metabolism, Free Radicals metabolism, Humans, Inflammation metabolism, Interleukin-8 biosynthesis, Lipoproteins, LDL physiology, Macrophage Inflammatory Proteins biosynthesis, Phospholipids metabolism, Chemokines metabolism, Lipoproteins, LDL metabolism, Monocytes metabolism, Platelet Membrane Glycoproteins metabolism, Receptors, G-Protein-Coupled metabolism, Urokinase-Type Plasminogen Activator genetics
Abstract

Background: We investigated whether the increase of urokinase-type plasminogen activator (uPA) monocyte expression and chemokine releases induced by oxidised low density lipoproteins (LDL), which participate to vascular tissue remodeling and to atherosclerotic plaque rupture, involved proinflammatory phospholipid products having platelet-activating factor (PAF)-like activity via the PAF-receptor pathway., Methods: uPA monocyte expression was stimulated by either copper ions-oxidised or O2*-/HO* free radical-oxidised LDL. The effects of PAF and oxidised LDL on the production of monocyte chemoattractant protein-1 and interleukin-8 were also examined., Results: Synthetic PAF significantly enhanced chemokine releases (P<0.001) without modifying uPA expression. Copper-oxidised LDL, which exhibit a higher content in lysophosphatidylcholines than free radical-oxidised LDL, induced a significantly higher enhancement in uPA expression (P<0.05). By contrast, free radical-oxidised LDL were more efficient than copper-oxidised LDL to increase chemokine releases (P<0.01). Oxidised LDL-enhanced uPA expressions were not altered by the PAF-receptor antagonist SR27417, whereas increases in chemokine releases induced by oxidised LDL and by PAF were abolished. PAF-acetylhydrolase activity was rapidly and largely inhibited in free radical-oxidised LDL when compared to copper-oxidised LDL, suggesting that free radical-oxidised LDL would contain a higher content in PAF-like products than copper-oxidised LDL., Conclusion: Our results indicated that PAF-like oxidation products are responsible for the monocyte chemokine releases, but did not contribute to the enhanced monocyte uPA expression by oxidised LDL., (Copyright 2004 Elsevier B.V.)

Published
2004
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7. Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits urokinase/urokinase-receptor expression and MMP-9 secretion by peripheral blood monocytes--a possible protective mechanism against atherothrombosis.

Author

Ganné F, Vasse M, Beaudeux JL, Peynet J, François A, Mishal Z, Chartier A, Tobelem G, Vannier JP, Soria J, and Soria C

Subjects
Arteriosclerosis drug therapy, Biological Transport drug effects, Cells, Cultured, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Microscopy, Confocal, Monocytes ultrastructure, Pyridines therapeutic use, Receptors, Urokinase Plasminogen Activator, Thrombosis drug therapy, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, Matrix Metalloproteinase 9 metabolism, Monocytes drug effects, Monocytes metabolism, Pyridines pharmacology, Receptors, Cell Surface biosynthesis, Urokinase-Type Plasminogen Activator biosynthesis
Abstract

It is now recognised that acute myocardial infarction results from the rupture of atherosclerotic plaques. Lymphocytes and macrophages, which infiltrate rupture sites, contribute to plaque degradation by expressing urokinase (u-PA) bound to cell membrane by urokinase receptor (u-PAR) and by secreting metalloproteinase MMP-9. We have previously demonstrated that the uptake of oxidised LDL (ox-LDL) by monocytes induces an increase of u-PA and u-PAR expression. The present study shows that the expression of u-PA and u-PAR induced by ox-LDL on monocyte surface is suppressed by cerivastatin (a synthetic inhibitor of HMG-CoA reductase, Bayer) from 2 nM. This leads to reduced plasmin generation and monocyte adhesion to vitronectin. Furthermore, higher concentrations of cerivastatin (50-100 nM) reduce the expression of u-PA and u-PAR on unstimulated monocytes. It also inhibits MMP-9 secretion but has no effect on TIMP-1 secretion, suggesting that the decrease in MMP-9 has a real protective effect on plaque stabilisation. The inhibitory effect of cerivastatin on u-PA expression and MMP-9 secretion can be explained by the inhibition of NF-kappa B translocation into the nucleus, as shown by immunofluorescence. As farnesyl-pyrophosphate reverses the effect of cerivastatin, it is postulated that these effects could also be due to the inhibition of Ras prenylation. This was confirmed by confocal microscopy, which shows the Ras delocalisation from the monocyte membrane. The cerivastatin-induced effects on monocyte functions could explain, at least in part, the protective effect of this drug against atherothrombotic events.

Published
2000

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