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(Hypertension. 2006;48:504.)
© 2006 American Heart Association, Inc.

Original Articles

C-Reactive Protein Upregulates Receptor for Advanced Glycation End Products Expression in Human Endothelial Cells

Yun Zhong; Shu-Hong Li; Shi-Ming Liu; Paul E. Szmitko; Xiao-Qing He; Paul W.M. Fedak; Subodh Verma

From the Toronto General Research Institute (Y.Z., S.-H.L., X.-Q.H., P.W.M.F.), Toronto, Ontario, Canada; Second Affiliated Hospital (Y.Z., S.-M.L., X.-Q.H.), Guangzhou Medical College, Guangzhou, China; and St Michael’s Hospital (P.E.S., S.V.), Toronto, Ontario, Canada.

Correspondence to Subodh Verma, Division of Cardiac Surgery, St Michael’s Hospital, 8th Floor, Bond Wing, 30 Bond St, Toronto, Ontario, Canada M5B 1W8. E-mail subodh.verma{at}sympatico.ca

The receptor for advanced glycation end products (RAGE) may play an important role in inflammatory processes and endothelial activation, likely to accelerate the processes of coronary atherosclerotic development, especially in diabetic patients. The factors that regulate arterial expression of RAGE are not completely clear. C-reactive protein (CRP) is identified as a key proinflammatory cytokine in patients with atherosclerosis. Therefore, we tested the hypothesis that RAGE expression in endothelial cells can be upregulated by CRP. Human saphenous vein endothelial cells were incubated with human recombinant CRP, free of sodium azide and endotoxin. RAGE protein expression was measured by flow-cytometric analysis and Western blotting. CRP caused a significant increase in RAGE protein expression at a dose as low as 5 µg/mL, with expression peaking at 24 to 48 hours after CRP incubation. The effects of modified monomeric CRP on RAGE protein expression were comparable with that of native pentameric CRP. At the mRNA level, CRP not only increased RAGE gene expression but also attenuated the degradation of RAGE mRNA. Furthermore, RNA interference of RAGE gene expression significantly decreased the level of macrophage chemoattractant protein 1, a key downstream mediator of CRP activity. Therefore, CRP at concentrations known to predict future vascular events upregulates RAGE expression in human endothelial cells at both the protein and mRNA level. Silencing of the RAGE gene prevents CRP–induced macrophage chemoattractant protein 1 activation. These data reinforce the mechanistic links among inflammation, endothelial dysfunction, and atherothrombosis.

Key Words: atherosclerosis • endothelial growth factors

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