Regulation of the endothelial plasminogen activator system by fluvastatin. Role of Rho family proteins, actin polymerisation and p38 MAP kinase
| Autor: | Egbert K. O. Kruithof, Richard J. Fish, Sylvie Dunoyer-Geindre |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
MAPK/ERK pathway
RHOA Indoles 030204 cardiovascular system & hematology Pharmacology RNA Small Interfering/metabolism p38 Mitogen-Activated Protein Kinases Fatty Acids Monounsaturated 0302 clinical medicine Cdc42 GTP-Binding Protein/metabolism RNA Small Interfering cdc42 GTP-Binding Protein ddc:616 0303 health sciences biology Reverse Transcriptase Polymerase Chain Reaction Alkyl and Aryl Transferases/antagonists & inhibitors Hematology HMG-CoA reductase Thiazolidines GTP-Binding Proteins/metabolism Signal transduction medicine.drug Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology RAC1 Indoles/metabolism/pharmacology Adenoviridae 03 medical and health sciences Plasminogen Activators Actins/chemistry GTP-Binding Proteins medicine Humans Plasminogen Activators/metabolism Adenoviridae/genetics Fluvastatin 030304 developmental biology Thiazolidines/metabolism Alkyl and Aryl Transferases Dose-Response Relationship Drug Activator (genetics) Endothelial Cells Fatty Acids Monounsaturated/metabolism/pharmacology Bridged Bicyclo Compounds Heterocyclic Molecular biology Actins Bicyclo Compounds Heterocyclic/metabolism P38 Mitogen-Activated Protein Kinases/metabolism biology.protein Hydroxymethylglutaryl-CoA Reductase Inhibitors Plasminogen activator Endothelial Cells/cytology |
| Zdroj: | Thrombosis and Haemostasis, Vol. 105, No 3 (2011) pp. 461-72 Thrombosis and haemostasis |
| ISSN: | 2567-689X 0340-6245 |
| Popis: | SummaryStatins are cholesterol-lowering drugs that exert pleiotropic effects which include changes in the plasminogen activation (PA) system of endothelial cells (EC). It was the objective of this study to investigate the signal transduction pathways by which statins increase the expression of tissue-type PA (t-PA) and decrease PA inhibitor type 1 (PAI-1) in human umbilical vein EC. Fluvastatin treatment increased t-PA expression more than 10-fold and reduced PAI-1 expression up to fivefold. This effect was mimicked by geranylgeranyl transferase inhibition. The role of geranylgeranylated small G-proteins of the Rho family was assessed by adenovirus-mediated expression of dominant negative (DN) RhoA, Cdc42 and Rac1 and by siRNA-mediated suppression of these proteins. DN-Cdc42 and DN-Rac1, as well as siRNA for Cdc42, increased t-PA expression, while DN-RhoA and DN-Rac1 decreased PAI-1 expression. Latrunculin B, an inhibitor of actin polymerisation, in-creased t-PA mRNA and reduced PAI-1 mRNA to the same extent as fluvastatin. Inhibition of p38, as well as p38α or p38β siRNA, reversed the effects of fluvastatin on t-PA expression. Treatment with p38β siRNA partially reversed the effect of fluvastatin on PAI-1, whereas p38α siRNA had no significant effect. Inhibition of jun kinase reduced basal and fluvastatin-induced t-PA expression to the same extent and increased PAI-1. MEK/ERK inhibition had no effect. In human EC, the fluvastatin-induced increase in t-PA is mediated by Cdc42 and, as with t-PA induced by inhibition of actin polymerisation, requires activation of p38MAP kinase. The mechanisms by which fluvastatin treatment reduces PAI-1 are different from those that increase t-PA. |
| Databáze: | OpenAIRE |
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