期刊
CARDIOVASCULAR RESEARCH
卷 57, 期 1, 页码 253-264出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/S0008-6363(02)00618-1
关键词
cholesterol; endothelial function; lipid metabolism; protein kinases; protein phosphorylation; statins
资金
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL050692] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR040197] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG017241, R37AG015052, R01AG015052] Funding Source: NIH RePORTER
- NHLBI NIH HHS [HL50692] Funding Source: Medline
- NIAMS NIH HHS [AR40197] Funding Source: Medline
- NIA NIH HHS [AG17241, AG15052] Funding Source: Medline
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. (C) 2002 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.
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