Cerivastatin, an Inhibitor of HMG-CoA Reductase, Inhibits Urokinase/Urokinase-receptor Expression and MMP-9 Secretion by Peripheral Blood Monocytes

Florence Ganné; Marc Vasse; Jean-Louis Beaudeux; Jacqueline Peynet; Arnaud François; Zohar Mishal; Antoine Chartier; Gérard Tobelem; Jean-Pierre Vannier; Jeannette Soria; Claudine Soria

doi:10.1055/s-0037-1614087

Thrombosis and Haemostasis, Table of Contents

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

Authors

Florence Ganné

¹From Laboratoire DIFEMA, Groupe de Recherches MERCI, Faculté de Médecine et de Pharmacie, Rouen, France
Marc Vasse

¹From Laboratoire DIFEMA, Groupe de Recherches MERCI, Faculté de Médecine et de Pharmacie, Rouen, France
Jean-Louis Beaudeux

²Laboratoire de Biochimie, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France
Jacqueline Peynet

²Laboratoire de Biochimie, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France
Arnaud François

³Service d’Anatomie et Cytologie Pathologiques, Hôpital C. Nicolle, Rouen, France
Zohar Mishal

⁴Service de Cytométrie en Flux, CNRS, Villejuif, France
Antoine Chartier

⁵Bayer Pharma, Puteaux, France
Gérard Tobelem

⁶Service d’Hématologie, Hôpital Lariboisière, Paris, France
Jean-Pierre Vannier

¹From Laboratoire DIFEMA, Groupe de Recherches MERCI, Faculté de Médecine et de Pharmacie, Rouen, France
Jeannette Soria

⁷Laboratoires de Biochimie et Ste Marie, Hôtel-Dieu, Paris, France
Claudine Soria

¹From Laboratoire DIFEMA, Groupe de Recherches MERCI, Faculté de Médecine et de Pharmacie, Rouen, France

²Laboratoire de Biochimie, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France

³Service d’Anatomie et Cytologie Pathologiques, Hôpital C. Nicolle, Rouen, France

⁴Service de Cytométrie en Flux, CNRS, Villejuif, France

⁵Bayer Pharma, Puteaux, France

⁶Service d’Hématologie, Hôpital Lariboisière, Paris, France

⁷Laboratoires de Biochimie et Ste Marie, Hôtel-Dieu, Paris, France

⁸Inserm U353, Hôpital St Louis, Paris, France

Abstract

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

Full Text

References

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