title: Rosuvastatin, a new HMG-CoA reductase inhibitor, upregulates endothelial nitric oxide synthase and protects from ischemic stroke in mice.
abstract: HMG-CoA reductase inhibitors (statins) are cholesterol-lowering drugs and reduce the risk of myocardial infarction and stroke. In this study we investigated whether rosuvastatin, a new, potent HMG-CoA reductase inhibitor, upregulates endothelial nitric oxide (NO) expression and activity and protects from cerebral ischaemia in mice. Endothelial cells in culture and 129/SV mice were chronically treated with rosuvastatin. The expression and activity of endothelial NO synthase (eNOS) was determined by reverse-transcriptase polymerase chain reaction (RT-PCR), Western blotting and arginine-citrulline assays. Cerebral ischaemia was induced by occlusion of the middle cerebral artery (MCAo) for 2 h and infarct size was determined after 22 h of reperfusion. Treatment of endothelial cells with rosuvastatin concentration- and time-dependently upregulated eNOS mRNA and protein expression. In aortas of 129/SV wild-type mice, treatment with 0.2, 2, and 20 mg kg(-1) rosuvastatin subcutaneously (s.c.) for 10 days significantly upregulated eNOS mRNA by 50, 142, and 205%, respectively. NOS activity was significantly increased by 75, 145, and 320%, respectively. Stroke volume after 2-h MCAo was reduced by 27, 56, and 50% (for 0.2, 2 and 20 mg kg(-1), respectively). Serum cholesterol and triglygeride levels were not significantly lowered by the treatment. The novel HMG-CoA reductase inhibitor rosuvastatin dose-dependently upregulates eNOS expression and activity and protects from cerebral ischaemia in mice. The effects are independent of changes in cholesterol levels and are equivalent or even superior to the protective effects by simvastatin and atorvastatin in this animal model.
authors.affiliation: Medizinische Klinik und Poliklinik der Universität des Saarlandes, Innere Medizin III, 66421 Homburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Laufs
authors.forename: Karen
authors.initials: K
authors.lastname: Gertz
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dirnagl
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
authors.forename: Matthias
authors.initials: M
authors.lastname: Endres
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D005464:Fluorobenzenes / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D051379:Mice; D008815:Mice, Inbred Strains; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D000068718:Rosuvastatin Calcium; D020521:Stroke / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D013449:Sulfonamides; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
chemical_list: D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018696:Neuroprotective Agents; D011743:Pyrimidines; D012333:RNA, Messenger; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D019001:Nitric Oxide Synthase