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

• Published in: Atherosclerosis Vol. 185; no. 2; pp. 240 - 245
• Main Authors: Hölschermann, Hans, Schuster, Daniel, Parviz, Behnoush, Haberbosch, Werner, Tillmanns, Harald, Muth, Heidrun
• Format: Journal Article
• Language: English
• Published: Ireland 01-04-2006
• Subjects: Cells, Cultured; Endothelium, Vascular - metabolism; Enzyme Activation - drug effects; Gene Expression - drug effects; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; I-kappa B Kinase - metabolism; I-kappa B Proteins - metabolism; Mevalonic Acid - pharmacology; NF-kappa B - antagonists & inhibitors; NF-kappa B - drug effects; NF-kappa B - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Pyridines - pharmacology; Signal Transduction; Thromboplastin - metabolism; Transcription Factor RelA - genetics; Transcription Factor RelA - metabolism; Transcription, Genetic; Transcriptional Activation - drug effects; Translocation, Genetic - drug effects; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0021-9150

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 kappaB (NF-kappaB) 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-kappaB 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-alpha. Statin-treatment prevented TNF-alpha-induced NF-kappaB binding activity, nuclear translocation of the NF-kappaB p65 subunit, as well as NF-kappaB controlled tissue factor (TF) gene transcription in cultured EC. IkappaBalpha phosphorylation and IkappaBalpha degradation, however, still occurred in statin-treated cells. TNF-alpha 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 IkappaBalpha phosphorylation nor IkappaBalpha degradation. These studies demonstrate that TNF-alpha-induced NF-kappaB activation is abrogated by statin treatment in HUVEC independently of the classical IKK-pathway but via inhibition of PI3-kinase/Akt signaling.