title: Anti-atherogenic effects of statins: Impact on angiopoietin-2 release from endothelial cells.
abstract: Beyond lipid lowering, statins are supposed to exert pleiotropic effects positively influencing the progression of atherosclerotic lesions. The development of such lesions is associated with increased release of angiopoietin-2 (Ang-2), an endothelial cell-specific protein growth factor stored in Weibel-Palade bodies (WPBs). The aim of our study was to examine whether statin pretreatment influences the release of Ang-2 from endothelial cells. Stimulation of HUVECs and HMVECs with PMA, thrombin or histamine resulted in significant release of Ang-2, as evidenced by ELISA. Pretreatment with simvastatin and mevastatin suppressed this release to basal level, while pravastatin had no effect. Simvastatin itself increased nitric oxide (NO, EC number 1.14.13.39) synthesis, measured by Griess reaction. Combining the statin pretreatment with the eNOS inhibitor L-NNA as well as bypassing the HMG-CoA reductase (EC number: 1.1.1.34) by adding mevalonic acid or geranyl pyrophosphate restored the exocytotic effect of PMA. Immunofluorescence microscopy showed that depletion of WPBs upon PMA stimulation ceased after pretreatment with simvastatin. This study demonstrates a potent suppressive effect of statins on the release of Ang-2 from endothelial cells. Regarding its harmful effects in the development of atherosclerotic lesions, our data provide further insight into the mechanisms of the anti-atherogenic potential of statins.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Germany. Electronic address: thilbert@uni-bonn.de.
authors.forename: Tobias
authors.initials: T
authors.lastname: Hilbert
authors.forename: Jens
authors.initials: J
authors.lastname: Poth
authors.forename: Stilla
authors.initials: S
authors.lastname: Frede
authors.forename: Sven
authors.initials: S
authors.lastname: Klaschik
authors.forename: Andreas
authors.initials: A
authors.lastname: Hoeft
authors.forename: Georg
authors.initials: G
authors.lastname: Baumgarten
authors.forename: Pascal
authors.initials: P
authors.lastname: Knuefermann
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D042702:Angiopoietin-2 / Q000378:metabolism*; D050197:Atherosclerosis / Q000517:prevention & control*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005089:Exocytosis / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors; D017035:Pravastatin / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology; D020302:Weibel-Palade Bodies / Q000187:drug effects* / Q000502:physiology
chemical_list: D000214:Acyl Coenzyme A; D042702:Angiopoietin-2; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; C012258:mevastatin; D009569:Nitric Oxide; D008148:Lovastatin; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III; D017035:Pravastatin
keywords: Angiopoietin-2; Atherosclerosis; DL-Mevalonic acid lactone (PubChem CID: 10428); Endothelial cells; Geranyl pyrophosphate ammonium salt (PubChem CID: 445995); Histamine (PubChem CID: 774); L-NNA (PubChem CID: 440005); Mevastatin (PubChem CID: 64715); Nitric oxide; Phorbol-12-myristate-13-acetate (PubChem CID: 27924); Pravastatin (PubChem CID: 16759173); Simvastatin (PubChem CID: 54454); Statins