Statins prevent NF-κB transactivation independently of the IKK-pathway in human endothelial cells

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 kappa B (NF-kappa B) 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-alpha-induced NF-kappa B signaling in human endothelial cells (EC). ECs were pre-incubated for 16 It with cerivastatin (10(-9) to 10(-7) M) or vehicle in the presence or absence of mevalonate, followed by stimulation with 20ng/ml TNF-alpha. Statin-treatment prevented TNF-a-induced NF-kappa B binding activity, nuclear translocation of the NF-kappa B p65 subunit, as well as NF-kappa B controlled tissue factor (TF) gene transcription in cultured EC. I kappa B alpha phosphorylation and I kappa B alpha. degradation, however, still occurred in statin-treated cells. TNF-a also activated phosphatidylinositol (PI)3-kinase, as reflected by phosphorylation of Akt. Statin treatment of cells abrogated TNF-alpha-induced Akt phosphorylation and p65 nuclear translocation. As observed with statins, inhibition of PI3-kinase activity by Ly294002 also blocked TNF-alpha-induced p65 translocation, but did not prevent I kappa B alpha phosphorylation nor I kappa B alpha degradation. These studies demonstrate that TNF-a-induced NF-kappa B activation is abrogated by statin treatment in HUVEC independently of the classical IKK-pathway but via inhibition of PI3-kinase/Akt signaling. (c) 2005 Elsevier Ireland Ltd. All rights reserved.