title: Beneficial vasoactive endothelial effects of fluvastatin: focus on prostacyclin and nitric oxide.
abstract: Statins are believed to exert beneficial effects against cardiovascular disease beyond correction of dyslipidemia. There are however still very sparse data on how individual statins interact with the production of vasoactive eicosanoids and nitric oxide (NO) in human vascular endothelial cells. Here we have determined how fluvastatin affects the mRNA expression of genes associated with vascular reactivity as well as the formation of two major vasodilators, prostacyclin (PGI2) and NO, in human endothelial cells. Also, the influence of fluvastatin on arterial resistance was assessed in isolated small arteries. We show that the promoter activity of prostacyclin synthase (PTGIS), the mRNA expression of PTGIS and endothelial nitric oxide synthase (eNOS), and the production of PGI2 and NO are significantly induced by fluvastatin. Also, strong rapid dilatation ex vivo was observed, with the equal contribution of PGI2 and NO. Our findings in cell culture experiments and in isolated human arteries indicate that fluvastatin-evoked endothelium-derived vasodilator production may confer protection of the endothelial cells via both acute and long-term effects of fluvastatin treatment. If these effects take place in vivo, we suggest a protective pleiotropic role of fluvastatin on the cardiovascular system, particularly at the level of the vascular endothelium, to ameliorate the process of atherogenesis and in the acute manner to reduce vascular tone.
authors.affiliation: Division of Clinical Pharmacology C1:68, Department of Laboratory Medicine, Karolinska University Hospital, 141 86, Stockholm, Sweden. Cristine.Skogastierna@ki.se
authors.forename: Cristine
authors.initials: C
authors.lastname: Skogastierna
authors.forename: Leonid
authors.initials: L
authors.lastname: Luksha
authors.forename: Karolina
authors.initials: K
authors.lastname: Kublickiene
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; D001158:Arteries / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005260:Female; D000077340:Fluvastatin; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007211:Indoles / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D050151:Subcutaneous Fat / Q000098:blood supply*; D014162:Transfection; D015854:Up-Regulation; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D012333:RNA, Messenger; D014665:Vasodilator Agents; D009569:Nitric Oxide; D000077340:Fluvastatin; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C472456:PTGIS protein, human