title: Withdrawal of statin treatment abrogates stroke protection in mice.
abstract: OBJECTIVE
  Statins (3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors) reduce stroke damage independent of lipid lowering by upregulation of endothelial nitric oxide synthase (eNOS). Acute withdrawal of statin treatment may suppress endothelial NO production and impair vascular function.
  
  
  METHODS
  To test this hypothesis, we treated 129/SV mice with atorvastatin (10 mg/kg) for 14 days and then withdrew treatment.
  
  
  RESULTS
  Treatment with atorvastatin conferred stroke protection by 40% after filamentous occlusion of the middle cerebral artery followed by reperfusion. Withdrawal of statin treatment, however, resulted in the loss of stroke protection after 2 and 4 days. In mouse aortas and brain vasculature, statins upregulated eNOS message 2.3- and 1.7-fold, respectively, as measured by reverse transcription-polymerase chain reaction. Withdrawal of statins resulted in 5- and 2.7-fold downregulation of eNOS in aorta and brain, respectively, after 2 days. Statin treatment decreased RhoA GTPase membrane expression to 48%, while withdrawal of statins resulted in 4-fold increase of RhoA in the membrane. Moreover, platelet factor 4 and beta-thromboglobulin in plasma were significantly downregulated by statin treatment, but withdrawal of statins resulted in a 2.9- and 3.1-fold upregulation after 2 days, respectively. Thrombus formation induced by ligature of the inferior vena cava was significantly reduced by statin treatment. When statin treatment was withdrawn, however, protection was lost between 2 and 4 days.
  
  
  CONCLUSIONS
  Acute termination of statin treatment results in a rapid loss of protection in mouse models of cerebral ischemia and thrombus formation independent of lipid lowering. In patients with acute or impending stroke, withdrawal of statins may impair outcome.
authors.affiliation: Klinik und Poliklinik für Neurologie, Charité, Humboldt-Universität Berlin, Berlin, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Gertz
authors.forename: Ulrich
authors.initials: U
authors.lastname: Laufs
authors.forename: Ute
authors.initials: U
authors.lastname: Lindauer
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dirnagl
authors.forename: Matthias
authors.initials: M
authors.lastname: Endres
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000473:pathology; D000069059:Atorvastatin; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects*; D001921:Brain / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D002545:Brain Ischemia / Q000139:chemically induced / Q000517:prevention & control; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D006538:Heptanoic Acids / Q000009:adverse effects* / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D008026:Ligation; D051379:Mice; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D015539:Platelet Activation / Q000187:drug effects; D011758:Pyrroles / Q000009:adverse effects* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020521:Stroke / Q000139:chemically induced* / Q000517:prevention & control; D013375:Substance Withdrawal Syndrome; D014682:Vena Cava, Inferior; D020246:Venous Thrombosis / Q000139:chemically induced / Q000473:pathology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D012333:RNA, Messenger; D000069059:Atorvastatin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D020742:rhoA GTP-Binding Protein