title: HMG-CoA reductase inhibitors promote cholesterol-dependent Akt/PKB translocation to membrane domains in endothelial cells.
abstract: OBJECTIVE
  Recent results have shown that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors referred to as statins rapidly activate the protein kinase Akt/PKB in endothelial cells (ECs) and endothelial precursor cells (EPCs). This pathway is critical for cellular responses that contribute to angiogenesis and EC function including nitric oxide production, cellular survival and migration.
  
  
  METHODS
  Here we tested whether statins control the translocation of recombinant and endogenous Akt to the plasma membrane of endothelial cells in a cholesterol-dependent manner.
  
  
  RESULTS
  Low doses of statins rapidly induce the translocation of Akt to discrete sites in endothelial cell plasma membrane that colocalize with F-actin-positive, focal adhesion kinase (FAK)-negative lamellipodia and filopodia. This translocation event requires the lipid-binding, pleckstrin homology domain of Akt. Treatment with phosphoinositide 3-kinase (PI 3-kinase) inhibitors or the HMG-CoA reductase reaction product L-mevalonate blocks the translocation of Akt in response to statin stimulation. Furthermore, the ability of statins to promote Akt activation and translocation to the membrane is inhibited by cholesterol delivery to cells, but cholesterol loading had no effect on VEGF-induced Akt activation.
  
  
  CONCLUSIONS
  These results suggest that statin activation of Akt signaling is mediated by the translocation of Akt to cholesterol-sensitive membrane structures within activated ECs.
authors.affiliation: Division of Cardiovascular Research, St. Elizabeth's Medical Center of Boston, Tufts University School of Medicine, 736 Cambridge Street, Boston, MA 02135, USA.
authors.forename: Adriane
authors.initials: A
authors.lastname: Skaletz-Rorowski
authors.forename: Mohini
authors.initials: M
authors.lastname: Lutchman
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kureishi
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Faust
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D018613:Microscopy, Confocal; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019821:Simvastatin / Q000494:pharmacology*; D014178:Translocation, Genetic / Q000187:drug effects; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D006903:Hydroxymethylglutaryl CoA Reductases; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019821:Simvastatin; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human