C-reactive protein activates the nuclear factor-κB signal transduction pathway in saphenous vein endothelial cells: Implications for atherosclerosis and restenosis

Subodh Verma, Mitesh V. Badiwala, Richard D. Weisel, Shu Hong Li, Chao Hung Wang, Paul W.M. Fedak, Ren Ke Li, Donald A.G. Mickle, Alexander Wahba, Carmelo A. Milano, Jakob Vinten-Johansen, Y. Joseph Woo

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

Abstract

Objectives: Elevated levels of C-reactive protein are one of the strongest prognostic factors in atherosclerosis. In addition to predicting vascular disease, C-reactive protein may directly facilitate the development of a proinflammatory and proatherosclerotic phenotype. Recent studies have demonstrated marked up-regulation of various adhesion molecules and inflammatory responses in endothelial cells subjected to C-reactive protein. The nuclear factor-κB signal transduction is known to play a key role in the expression of these proatherogenic entities. This study examines the direct effects of C-reactive protein on nuclear factor-κB activation and related mechanisms in saphenous vein endothelial cells. Methods: The activation of nuclear factor-κB was determined by confocal microscopy assessing the nuclear localization of nuclear factor-κB in endothelial cells incubated with C-reactive protein (50 μg/mL) for 30 minutes and 3 hours. Cells not incubated with C-reactive protein were used as negative controls, and cells incubated with tumor necrosis factor-α (10 ng/mL) for 15 minutes were used as positive controls in all studies. The degradation of IκB-α and IκB-β was assessed by Western blotting of the cell lysates obtained from cells incubated with human recombinant C-reactive protein (50 μg/mL) for 15 minutes, 30 minutes, and 1 hour. Results: Nuclear factor-κB nuclear translocation in endothelial cells increased significantly after 30 minutes of incubation with C-reactive protein (P < .01). Nuclear localization of nuclear factor-κB returned to baseline levels after 3 hours of incubation with C-reactive protein. Incubation with C-reactive protein resulted in degradation of IκB-α that was maximal at 30 minutes (P < .05). C-reactive protein showed no significant effect on IκB-β degradation. Conclusions: These data demonstrate, for the first time, that C-reactive protein activates the nuclear, factor-κB signal transduction pathway in endothelial cells. Degradation of IκB-α, but not IκB-β, seems to be the major pathway leading to nuclear factor-κB nuclear translocation and activation induced by C-reactive protein. These data support the concept that C-reactive protein, at concentrations known to predict diverse vascular insults, directly facilitates a proinflammatory and proatherosclerotic phenotype through activation of nuclear factor-κB. These data have important implications for saphenous vein atherosclerosis in patients with elevated C-reactive protein levels.

Original languageEnglish
Pages (from-to)1886-1891
Number of pages6
JournalJournal of Thoracic and Cardiovascular Surgery
Volume126
Issue number6
DOIs
StatePublished - Dec 2003
Externally publishedYes

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