Advertisement

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

      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

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Karin M.
        • Delhase M.
        The IκB-kinase (IKK) and NF-κB: key elements of proinflammatory signaling.
        Semin Immunol. 2000; 12: 85-98
        • Verma I.M.
        • Stevenson J.K.
        • Schwarz E.M.
        • Van Antwerp D.
        • Miyamoto S.
        Rel/NF-κB family: intimate tales of association and dissociation.
        Genes Develop. 1995; 15: 2723-2735
        • Mercurio F.
        • Manning A.M.
        Multiple signals converging on NF-κB.
        Curr Opin Cell Biol. 1999; 11: 226-232
        • Jaffe E.A.
        • Nachman R.L.
        • Becker C.G.
        • et al.
        Culture of human endothelial cells derived from umbilical veins identification by morphologic and immunologic criteria.
        J Clin Invest. 1973; 52: 2745-2751
        • Hölschermann H.
        • Dürfeld F.
        • Haberbosch W.
        • et al.
        Cyclosporin A inhibits tissue factor expression in monocytes/macrophages.
        Blood. 1996; 88: 3837-3845
        • Chomczynski P.
        • Sacchi N.
        Singel step method of RNA-isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.
        Anal Biochem. 1987; 162: 156-159
        • Hilgendorff A.
        • Muth H.
        • Hölschermann H.
        • et al.
        Statins differ in their ability to block NF-κB activation in human blood monocytes.
        Clin Pharm Therap. 2003; 41: 397-401
        • Patel T.R.
        • Corbett S.A.
        Simvastatin supresses LPS-induced Akt phosphorylation in the human monocyte cell line THP-1.
        J Surg Res. 2004; 116: 116-120
        • Fukuyama R.
        • Fujita T.
        • Azuma Y.
        • et al.
        Statins inhibit osteoblast migration by inhibiting Rac–Akt signaling.
        Biochem Biophys Res Commun. 2004; 315: 636-642
        • Hippenstiel S.
        • Schmeck B.
        • Suttorp N.
        • et al.
        Reduction of tumor necrosis factor-α (TNF-α) related nuclear factor-κB (NF-κB) translocation but not inhibitorκ-B (Iκ-B)-degradation by Rho protein inhibition in human endothelial cells.
        Biochem Pharmacol. 2002; 64: 971-979
        • Dimmeler S.
        • Aicher A.
        • Vasa M.
        • et al.
        HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI3-kinase/Akt pathway.
        J Clin Invest. 2001; 108: 391-397