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.
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Published online: July 29, 2005
Accepted: June 20, 2005
Received in revised form: June 15, 2005
Received: July 29, 2004
© 2005 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.