© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
HMG-CoA reductase inhibitors promote cholesterol-dependent Akt/PKB translocation to membrane domains in endothelial cells
aDivision of Cardiovascular Research, St. Elizabeth's Medical Center of Boston, Tufts University School of Medicine, 736 Cambridge Street, Boston, MA 02135, USA
bDepartment of Cell Biology, SGM 411, Harvard Medical, 240 Longwood Avenue, Boston, MA 02111, USA
cInstitute for Arteriosclerosis Research, University of Muenster, Domagkstrasse 3, 48149 Muenster, Germany
dDepartment of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA
eDepartment of Physiology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA
fMolecular Cardiology/CVI, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA
kwalsh{at}world.std.com
* Corresponding author. Molecular Cardiology/CVI, Boston University School of Medicine, 715 Albany Street, W611, Boston, MA 02118, USA. Tel.: +1-617-414-2392; fax: +1-617-414-2391.
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.
KEYWORDS Cholesterol; Endothelial function; Lipid metabolism; Protein kinases; Protein phosphorylation; Statins
1 Both authors contributed equally to this work.
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