title: Regulation of the endothelial plasminogen activator system by fluvastatin. Role of Rho family proteins, actin polymerisation and p38 MAP kinase.
abstract: Statins 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 five-fold. 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, increased 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.
authors.affiliation: Division of Angiology and Hemostasis, Department of Internal Medicine, Geneva University Hospital, Geneva, Switzerland.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dunoyer-Geindre
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Fish
authors.forename: Egbert K O
authors.initials: EK
authors.lastname: Kruithof
mesh_terms: D000199:Actins / Q000737:chemistry*; D000256:Adenoviridae / Q000235:genetics; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism* / Q000494:pharmacology; D000077340:Fluvastatin; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000378:metabolism* / Q000494:pharmacology; D010960:Plasminogen Activators / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053778:Thiazolidines / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000199:Actins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D034741:RNA, Small Interfering; D053778:Thiazolidines; D000077340:Fluvastatin; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D048051:p38 Mitogen-Activated Protein Kinases; D010960:Plasminogen Activators; D019204:GTP-Binding Proteins; D020764:cdc42 GTP-Binding Protein; C037068:latrunculin B