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Thromb Haemost 2000; 84(04): 680-688
DOI: 10.1055/s-0037-1614087
Review Article
Schattauer GmbH

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
Florence Ganné
1   From Laboratoire DIFEMA, Groupe de Recherches MERCI, Faculté de Médecine et de Pharmacie, Rouen, France
,
Marc Vasse
1   From Laboratoire DIFEMA, Groupe de Recherches MERCI, Faculté de Médecine et de Pharmacie, Rouen, France
,
Jean-Louis Beaudeux
2   Laboratoire de Biochimie, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France
,
Jacqueline Peynet
2   Laboratoire de Biochimie, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France
,
Arnaud François
3   Service d’Anatomie et Cytologie Pathologiques, Hôpital C. Nicolle, Rouen, France
,
Zohar Mishal
4   Service de Cytométrie en Flux, CNRS, Villejuif, France
,
Antoine Chartier
5   Bayer Pharma, Puteaux, France
,
Gérard Tobelem
6   Service d’Hématologie, Hôpital Lariboisière, Paris, France
,
Jean-Pierre Vannier
1   From Laboratoire DIFEMA, Groupe de Recherches MERCI, Faculté de Médecine et de Pharmacie, Rouen, France
,
Jeannette Soria
7   Laboratoires de Biochimie et Ste Marie, Hôtel-Dieu, Paris, France
,
Claudine Soria
1   From Laboratoire DIFEMA, Groupe de Recherches MERCI, Faculté de Médecine et de Pharmacie, Rouen, France
2   Laboratoire de Biochimie, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France
3   Service d’Anatomie et Cytologie Pathologiques, Hôpital C. Nicolle, Rouen, France
4   Service de Cytométrie en Flux, CNRS, Villejuif, France
5   Bayer Pharma, Puteaux, France
6   Service d’Hématologie, Hôpital Lariboisière, Paris, France
7   Laboratoires de Biochimie et Ste Marie, Hôtel-Dieu, Paris, France
8   Inserm U353, Hôpital St Louis, Paris, France
› Author AffiliationsThe authors thank Zohar Mishal for confocal microscopy analysis, Elisabeth Legrand and Damien Genty for their excellent technical assistance, Jean-Philippe Collet for helpful discussions, and Richard Medeiros for his advice in editing the manuscript.
Further Information

Publication History

Received 08 June 1999

Accepted after resubmission 04 May 2000

Publication Date:
11 December 2017 (online)

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Summary

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.

Key words

HMG-CoA reductase inhibitor - urokinase - metalloproteinase - atherothrombosis - monocyte
 

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