FcgammaRIIB mediates C-reactive protein inhibition of endothelial NO synthase.
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 Fcgamma receptors, causes parallel okadaic acid-sensitive loss of eNOS function, FcgammaRIIB expression is demonstrable in endothelium, and heterologous expression studies reveal that CRP antagonism of eNOS requires FcgammaRIIB. In FcgammaRIIB(+/+) mice, CRP blunts acetylcholine-induced increases in carotid artery vascular conductance; in contrast, CRP enhances acetylcholine responses in FcgammaRIIB(-/-) mice. Thus FcgammaRIIB mediates CRP inhibition of eNOS via PP2A, providing a mechanistic link between CRP and endothelial dysfunction.
Mineo
Chieko
C
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Gormley
Andrew K
AK
Yuhanna
Ivan S
IS
Osborne-Lawrence
Sherri
S
Gibson
Linda L
LL
Hahner
Lisa
L
Shohet
Ralph V
RV
Black
Steven
S
Salmon
Jane E
JE
Samols
David
D
Karp
David R
DR
Thomas
Gail D
GD
Shaul
Philip W
PW
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002097:C-Reactive Protein / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors*; D010749:Phosphoprotein Phosphatases / Q000502:physiology; D010766:Phosphorylation; D017452:Receptors, IgG / Q000502:physiology*; D000683:Serum Amyloid P-Component / Q000494:pharmacology; D020298:U937 Cells
C499172:Fcgr2b protein, mouse; D017452:Receptors, IgG; D000683:Serum Amyloid P-Component; D009569:Nitric Oxide; D002097:C-Reactive Protein; D052250:Nitric Oxide Synthase Type III; D010749:Phosphoprotein Phosphatases; D000109:Acetylcholine