title: Coupling of Fcγ receptor I to Fcγ receptor IIb by SRC kinase mediates C-reactive protein impairment of endothelial function.
abstract: BACKGROUND
  Elevations in C-reactive protein (CRP) are associated with increased cardiovascular disease risk and endothelial dysfunction. CRP antagonizes endothelial nitric oxide synthase (eNOS) through processes mediated by the IgG receptor Fcγ receptor IIB (FcγRIIB), its immunoreceptor tyrosine-based inhibitory motif, and SH2 domain-containing inositol 5'-phosphatase 1. In mice, CRP actions on eNOS blunt carotid artery re-endothelialization.
  
  
  OBJECTIVE
  How CRP activates FcγRIIB in endothelium is not known. We determined the role of Fcγ receptor I (FcγRI) and the basis for coupling of FcγRI to FcγRIIB in endothelium.
  
  
  RESULTS
  In cultured endothelial cells, FcγRI-blocking antibodies prevented CRP antagonism of eNOS, and CRP activated Src via FcγRI. CRP-induced increases in FcγRIIB immunoreceptor tyrosine-based inhibitory motif phosphorylation and SH2 domain-containing inositol 5'-phosphatase 1 activation were Src-dependent, and Src inhibition prevented eNOS antagonism by CRP. Similar processes mediated eNOS antagonism by aggregated IgG used to mimic immune complex. Carotid artery re-endothelialization was evaluated in offspring from crosses of CRP transgenic mice (TG-CRP) with either mice lacking the γ subunit of FcγRI (FcRγ(-/-)) or FcγRIIB(-/-) mice. Whereas re-endothelialization was impaired in TG-CRP vs wild-type, it was normal in both FcRγ(-/-); TG-CRP and FcγRIIB(-/-); TG-CRP mice.
  
  
  CONCLUSIONS
  CRP antagonism of eNOS is mediated by the coupling of FcγRI to FcγRIIB by Src kinase and resulting activation of SH2 domain-containing inositol 5'-phosphatase 1, and consistent with this mechanism, both FcγRI and FcγRIIB are required for CRP to blunt endothelial repair in vivo. Similar mechanisms underlie eNOS antagonism by immune complex. FcγRI and FcγRIIB may be novel therapeutic targets for preventing endothelial dysfunction in inflammatory or immune complex-mediated conditions.
authors.affiliation: Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Sundgren
authors.forename: Weifei
authors.initials: W
authors.lastname: Zhu
authors.forename: Ivan S
authors.initials: IS
authors.lastname: Yuhanna
authors.forename: Ken L
authors.initials: KL
authors.lastname: Chambliss
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ahmed
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanigaki
authors.forename: Michihisa
authors.initials: M
authors.lastname: Umetani
authors.forename: Chieko
authors.initials: C
authors.lastname: Mineo
authors.forename: Philip W
authors.initials: PW
authors.lastname: Shaul
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism*; D020212:Carotid Artery Injuries / Q000201:enzymology* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002417:Cattle; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D004789:Enzyme Activation; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D011817:Rabbits; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000936:Antigen-Antibody Complex; C499173:FCGR2B protein, human; C485701:Fcgr1 protein, mouse; C499172:Fcgr2b protein, mouse; D017452:Receptors, IgG; D002097:C-Reactive Protein; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019061:src-Family Kinases; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases