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(Circulation Research. 2005;97:1124.)
© 2005 American Heart Association, Inc.

Molecular Medicine

FcRIIB 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

From the Departments of Pediatrics (C.M., A.K.G., I.S.Y., S.O.-L., L.L.G., L.H., P.W.S.) and Internal Medicine (R.V.S., D.R.K., G.D.T.), University of Texas Southwestern Medical Center, Dallas; Department of Medicine (J.E.S.), Cornell University Weill Medical College, New York, NY; and Department of Biochemistry (S.B., D.S.), Case Western Reserve University School of Medicine, Cleveland, Ohio.

Correspondence to Philip W. Shaul, Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX. E-mail philip.shaul{at}utsouthwestern.edu

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 Fc receptors, causes parallel okadaic acid–sensitive loss of eNOS function, FcRIIB expression is demonstrable in endothelium, and heterologous expression studies reveal that CRP antagonism of eNOS requires FcRIIB. In FcRIIB^+/+ mice, CRP blunts acetylcholine-induced increases in carotid artery vascular conductance; in contrast, CRP enhances acetylcholine responses in FcRIIB^–/– mice. Thus FcRIIB mediates CRP inhibition of eNOS via PP2A, providing a mechanistic link between CRP and endothelial dysfunction.

Key Words: C-reactive protein • endothelial NO synthase • Fc receptor • PP2A

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