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J Thorac Cardiovasc Surg 2003;126:1886-1891
© 2003 The American Association for Thoracic Surgery

Cardiopulmonary support and physiology

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

^a Division of Cardiac Surgery, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada

Read at the Eighty-third Annual Meeting of The American Association for Thoracic Surgery, Boston, Mass, May 4-7, 2003.

Received for publication May 2, 2003; accepted for publication July 22, 2003.

^* Address for correspondence: Subodh Verma, MD, PhD, Division of Cardiac Surgery, 14 EN-215, 200 Elizabeth St, Toronto General Hospital, Toronto, ON, Canada M5G 2C4
subodh.verma{at}sympatico.ca

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-B 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-B activation and related mechanisms in saphenous vein endothelial cells.

METHODS: The activation of nuclear factor-B was determined by confocal microscopy assessing the nuclear localization of nuclear factor-B 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- (10 ng/mL) for 15 minutes were used as positive controls in all studies. The degradation of IB- and IB-ß 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-B nuclear translocation in endothelial cells increased significantly after 30 minutes of incubation with C-reactive protein (P < .01). Nuclear localization of nuclear factor-B returned to baseline levels after 3 hours of incubation with C-reactive protein. Incubation with C-reactive protein resulted in degradation of IB- that was maximal at 30 minutes (P < .05). C-reactive protein showed no significant effect on IB-ß degradation.

CONCLUSIONS: These data demonstrate, for the first time, that C-reactive protein activates the nuclear factor-B signal transduction pathway in endothelial cells. Degradation of IB-, but not IB-ß, seems to be the major pathway leading to nuclear factor-B 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-B. These data have important implications for saphenous vein atherosclerosis in patients with elevated C-reactive protein levels.

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