title: Blockade of geranylgeranylation by rosuvastatin upregulates eNOS expression in human venous endothelial cells.
abstract: Endothelial dysfunction is associated with a reduction in nitric oxide (NO) bioavailability. Positive effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on the improvement of endothelial dysfunction have been shown. We investigated the effects of rosuvastatin and isoprenoid metabolites on endothelial NO synthase (eNOS) mRNA and protein expression in human umbilical venous endothelial cells after exposure to 10(-8)-10(-5) mol/l rosuvastatin for 8 and 12 h. Cell viability was not significantly altered after exposure to the statin for 12h. In a concentration-dependent manner, rosuvastatin upregulated eNOS mRNA and protein expression. The effects on eNOS expression mediated through rosuvastatin could be reversed by treatment with mevalonate indicating inhibition of HMG-CoA reductase as the underlying mechanism. Treatment with geranylgeranylpyrophosphate, but not farnesylpyrophosphate, reversed the increase of eNOS expression induced by rosuvastatin. Rosuvastatin may have beneficial effects on endothelial dysfunction associated with cardiovascular diseases beyond its effects on lowering cholesterol.
authors.affiliation: Department of Internal Medicine B, Ernst Moritz Arndt University, Greifswald, Germany. martin.landsberger@uni-greifswald.de
authors.forename: Martin
authors.initials: M
authors.lastname: Landsberger
authors.forename: Franziska
authors.initials: F
authors.lastname: Jantzen
authors.forename: Stephanie
authors.initials: S
authors.lastname: Könemann
authors.forename: Stephan B
authors.initials: SB
authors.lastname: Felix
mesh_terms: D002470:Cell Survival; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D005464:Fluorobenzenes / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D017368:Protein Prenylation; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D052250:Nitric Oxide Synthase Type III