Abstract
Statins have been linked to a wide range of vascular benefits, many of them are likely
to be due to attenuation of chronic vascular inflammation. Nuclear factor κB (NF-κB)
is one of the key regulators of transcription of a variety of genes involved in immune
and inflammatory responses. Therefore, we investigated the effect of statins on TNF-α-induced
NF-κB signaling in human endothelial cells (EC).
ECs were pre-incubated for 16 h with cerivastatin (10−9 to 10−7 M) or vehicle in the presence or absence of mevalonate, followed by stimulation with
20 ng/ml TNF-α. Statin-treatment prevented TNF-α-induced NF-κB binding activity, nuclear
translocation of the NF-κB p65 subunit, as well as NF-κB controlled tissue factor
(TF) gene transcription in cultured EC. IκBα phosphorylation and IκBα degradation,
however, still occurred in statin-treated cells. TNF-α also activated phosphatidylinositol
(PI)3-kinase, as reflected by phosphorylation of Akt. Statin treatment of cells abrogated
TNF-α-induced Akt phosphorylation and p65 nuclear translocation. As observed with
statins, inhibition of PI3-kinase activity by Ly294002 also blocked TNF-α-induced
p65 translocation, but did not prevent IκBα phosphorylation nor IκBα degradation.
These studies demonstrate that TNF-α-induced NF-κB activation is abrogated by statin
treatment in HUVEC independently of the classical IKK-pathway but via inhibition of
PI3-kinase/Akt signaling.
Keywords
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Article info
Publication history
Published online: July 29, 2005
Accepted:
June 20,
2005
Received in revised form:
June 15,
2005
Received:
July 29,
2004
Identification
Copyright
© 2005 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
