FcγRIIB Mediates C-Reactive Protein Inhibition of Endothelial NO Synthase

• Published in: Circulation research Vol. 97; no. 11; pp. 1124 - 1131
• Main Authors: Mineo, Chieko, Gormley, Andrew K, Yuhanna, Ivan S, Osborne-Lawrence, Sherri, Gibson, Linda L, Hahner, Lisa, Shohet, Ralph V, Black, Steven, Salmon, Jane E, Samols, David, Karp, David R, Thomas, Gail D, Shaul, Philip W
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 25.11.2005; Lippincott
• Subjects: Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Vertebrates: cardiovascular system; C-reactive protein; Enzyme; Fcγ receptor; PP2A; Synthase; Endothelium; Vertebrata; Mammalia; Circulatory system; Inhibition; C reactive protein; endothelial NO synthase; Biological receptor
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000194323.77203.fe

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 FcγRIIB mice. Thus FcγRIIB mediates CRP inhibition of eNOS via PP2A, providing a mechanistic link between CRP and endothelial dysfunction.