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HMG CoA reductase inhibitors reduce plasminogen activator inhibitor-1 expression by human vascular smooth muscle and endothelial cells. 2000

T Bourcier, and P Libby
Brigham & Women's Hospital and Harvard Medical School, Department of Medicine, Vascular Medicine and Atherosclerosis Unit, Boston, MA 02115, USA.

The clinical benefit of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may derive from a qualitative, functional change in atherosclerotic lesions in addition to their lipid-lowering properties. We examined whether statins altered expression of the major determinants of fibrinolytic balance, plasminogen activator inhibitor-1 (PAI-1), and tissue-type plasminogen activator (tPA) in human vascular smooth muscle (SMC) and endothelial (EC) cells. Simvastatin reduced levels of PAI-1 antigen released from SMCs and ECs stimulated with platelet-derived growth factor or transforming growth factor-beta (IC(50) approximately 1 micromol/L). Levels of EC-derived tPA increased 2-fold over the same concentrations of simvastatin that inhibited release of PAI-1. Simvastatin's inhibitory effect was mimicked by C3 exoenzyme and prevented by geranylgeranyl pyrophosphate, but not by farnesyl pyrophosphate, suggesting the involvement of geranylgeranyl-modified intermediates. Decreased PAI-1 antigen was correlated with reduced mRNA transcription and activity of the PAI-1 promoter. By inhibiting expression of PAI-1 from SMCs and ECs while increasing expression of tPA from ECs, simvastatin may alter the local fibrinolytic balance within the vessel wall toward increased fibrinolytic capacity that, in turn, would reduce thrombotic risk after plaque rupture.

UI MeSH Term Description Entries
D009131 Muscle, Smooth, Vascular The nonstriated involuntary muscle tissue of blood vessels. Vascular Smooth Muscle,Muscle, Vascular Smooth,Muscles, Vascular Smooth,Smooth Muscle, Vascular,Smooth Muscles, Vascular,Vascular Smooth Muscles
D011106 Polyisoprenyl Phosphates Phosphoric or pyrophosphoric acid esters of polyisoprenoids. Isoprenoid Phosphates,Terpene Phosphates,Phosphates, Isoprenoid,Phosphates, Polyisoprenyl,Phosphates, Terpene
D011401 Promoter Regions, Genetic DNA sequences which are recognized (directly or indirectly) and bound by a DNA-dependent RNA polymerase during the initiation of transcription. Highly conserved sequences within the promoter include the Pribnow box in bacteria and the TATA BOX in eukaryotes. rRNA Promoter,Early Promoters, Genetic,Late Promoters, Genetic,Middle Promoters, Genetic,Promoter Regions,Promoter, Genetic,Promotor Regions,Promotor, Genetic,Pseudopromoter, Genetic,Early Promoter, Genetic,Genetic Late Promoter,Genetic Middle Promoters,Genetic Promoter,Genetic Promoter Region,Genetic Promoter Regions,Genetic Promoters,Genetic Promotor,Genetic Promotors,Genetic Pseudopromoter,Genetic Pseudopromoters,Late Promoter, Genetic,Middle Promoter, Genetic,Promoter Region,Promoter Region, Genetic,Promoter, Genetic Early,Promoter, rRNA,Promoters, Genetic,Promoters, Genetic Middle,Promoters, rRNA,Promotor Region,Promotors, Genetic,Pseudopromoters, Genetic,Region, Genetic Promoter,Region, Promoter,Region, Promotor,Regions, Genetic Promoter,Regions, Promoter,Regions, Promotor,rRNA Promoters
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D004730 Endothelium, Vascular Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components. Capillary Endothelium,Vascular Endothelium,Capillary Endotheliums,Endothelium, Capillary,Endotheliums, Capillary,Endotheliums, Vascular,Vascular Endotheliums
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D012717 Sesquiterpenes Fifteen-carbon compounds formed from three isoprenoid units with general formula C15H24. Farnesanes,Farnesene,Farnesenes,Sesquiterpene,Sesquiterpene Derivatives,Sesquiterpenoid,Sesquiterpenoids,Derivatives, Sesquiterpene
D014158 Transcription, Genetic The biosynthesis of RNA carried out on a template of DNA. The biosynthesis of DNA from an RNA template is called REVERSE TRANSCRIPTION. Genetic Transcription
D017395 Plasminogen Activator Inhibitor 1 A member of the serpin family of proteins. It inhibits both the tissue-type and urokinase-type plasminogen activators. PAI-1,SERPINE1 Protein,Serpin E1,Type 1 Plasminogen Activator Inhibitor,E1, Serpin,Protein, SERPINE1
D019161 Hydroxymethylglutaryl-CoA Reductase Inhibitors Compounds that inhibit HYDROXYMETHYLGLUTARYL COA REDUCTASES. They have been shown to directly lower CHOLESTEROL synthesis. HMG-CoA Reductase Inhibitor,HMG-CoA Reductase Inhibitors,Hydroxymethylglutaryl-CoA Reductase Inhibitor,Statin,Statins, HMG-CoA,Inhibitors, HMG-CoA Reductase,Inhibitors, Hydroxymethylglutaryl-CoA,Inhibitors, Hydroxymethylglutaryl-Coenzyme A,Statins,HMG CoA Reductase Inhibitor,HMG CoA Reductase Inhibitors,HMG-CoA Statins,Hydroxymethylglutaryl CoA Reductase Inhibitor,Hydroxymethylglutaryl CoA Reductase Inhibitors,Hydroxymethylglutaryl-CoA Inhibitors,Hydroxymethylglutaryl-Coenzyme A Inhibitors,Inhibitors, HMG CoA Reductase,Inhibitors, Hydroxymethylglutaryl CoA,Inhibitors, Hydroxymethylglutaryl Coenzyme A,Inhibitors, Hydroxymethylglutaryl-CoA Reductase,Reductase Inhibitor, Hydroxymethylglutaryl-CoA,Reductase Inhibitors, HMG-CoA,Reductase Inhibitors, Hydroxymethylglutaryl-CoA,Statins, HMG CoA

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