FcγRIIB mediates C-reactive protein inhibition of endothelial NO synthase

Chieko Mineo, Andrew K. Gormley, Ivan S. Yuhanna, Sherri Osborne-Lawrence, Linda L. Gibson, Lisa Hahner, Ralph V. Shohet, Steven Black, Jane E. Salmon, David Samols, David R. Karp, Gail D. Thomas, Philip W. Shaul

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

C-reactive protein (CRP) is an acute-phase reactant that is positively correlated with cardiovascular disease risk and endothelial dysfunction. Whether CRP has direct actions on endothelium and the mechanisms underlying such actions are unknown. Here we show in cultured endothelium that CRP prevents endothelial NO synthase (eNOS) activation by diverse agonists, resulting in the promotion of monocyte adhesion. CRP antagonism of eNOS occurs nongenomically and is attributable to blunted eNOS phosphorylation at Ser1179. Okadaic acid or knockdown of PP2A by short-interference RNA reverses CRP antagonism of eNOS, indicating a key role for the phosphatase. Aggregated IgG, the known ligand for Fcγ receptors, causes parallel okadaic acid-sensitive loss of eNOS function, FcγRIIB expression is demonstrable in endothelium, and heterologous expression studies reveal that CRP antagonism of eNOS requires FcγRIIB. In FcγRIIB+/+ mice, CRP blunts acetylcholine-induced increases in carotid artery vascular conductance; in contrast, CRP enhances acetylcholine responses in Fcγ-/- mice. Thus FcγRIIB mediates CRP inhibition of eNOS via PP2A, providing a mechanistic link between CRP and endothelial dysfunction.

Original languageEnglish (US)
Pages (from-to)1124-1131
Number of pages8
JournalCirculation research
Volume97
Issue number11
DOIs
StatePublished - Nov 1 2005

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Keywords

  • C-reactive protein
  • Endothelial NO synthase
  • Fcγ receptor
  • PP2A

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Mineo, C., Gormley, A. K., Yuhanna, I. S., Osborne-Lawrence, S., Gibson, L. L., Hahner, L., Shohet, R. V., Black, S., Salmon, J. E., Samols, D., Karp, D. R., Thomas, G. D., & Shaul, P. W. (2005). FcγRIIB mediates C-reactive protein inhibition of endothelial NO synthase. Circulation research, 97(11), 1124-1131. https://doi.org/10.1161/01.RES.0000194323.77203.fe