title: Influence of simvastatin on the thromboxane and prostacyclin pathways, in vitro and in vivo.
abstract: 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) are believed to exert beneficial effects against cardiovascular disease beyond correction of dyslipidemia. The aim of this combined in vitro and in vivo study was to investigate the influence of the commonly used simvastatin on prostacyclin and thromboxane A2, 2 prostaglandins with different cardiovascular effects, normally in homeostatic balance in the circulatory system. Single-dose administration of simvastatin significantly decreased urinary prostacyclin excretion of healthy volunteers (P < 0.01) and increased the ratio between thromboxane A2 and prostacyclin (2-fold increase, P < 0.01), as assessed by enzyme immunoassays of the corresponding metabolites in urine. Human vascular endothelial cells, exposed to corresponding concentrations of simvastatin and assayed in the same way, reduced the release of prostacyclin about 40% (P < 0.05), altered the transcriptional expression of cyclooxygenase and prostacyclin synthase as analyzed by real-time polymerase chain reaction, and reduced the prostacyclin synthase promoter activity by 50% (P < 0.05), evaluated in a luciferase reporter system. We speculate that simvastatin shifts the balance between thromboxane A2 and prostacyclin in favor of the thromboxane pathway in vivo, and after exposure to clinically relevant concentrations in vitro. This may have pathophysiological implications by promoting a prothrombotic state in the blood vessels.
authors.affiliation: Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden. cristine.skogastierna@ki.se
authors.forename: Cristine
authors.initials: C
authors.lastname: Skogastierna
authors.forename: Linda
authors.initials: L
authors.lastname: Björkhem-Bergman
authors.forename: Peter
authors.initials: P
authors.lastname: Bergman
authors.forename: Erik
authors.initials: E
authors.lastname: Eliasson
authors.forename: Anders
authors.initials: A
authors.lastname: Rane
authors.forename: Lena
authors.initials: L
authors.lastname: Ekström
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000652:urine; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism* / Q000652:urine; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D017930:Genes, Reporter; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007124:Immunoenzyme Techniques; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011401:Promoter Regions, Genetic / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000378:metabolism* / Q000652:urine; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
chemical_list: D015415:Biomarkers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013928:Thromboxane A2; D003577:Cytochrome P-450 Enzyme System; D019821:Simvastatin; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase