Cellular Biology Coupling of Fc Receptor I to Fc Receptor IIB by Src Kinase Mediates C-Reactive Protein Impairment of Endothelial Function

Rationale: 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 Fc receptor IIB (Fc RIIB), its immunoreceptor tyrosine-based inhibitory motif, and SH2 domaincontaining inositol 5 -phosphatase 1. In mice, CRP actions on eNOS blunt carotid artery re-endothelialization. Objective: How CRP activates Fc RIIB in endothelium is not known. We determined the role of Fc receptor I (Fc RI) and the basis for coupling of Fc RI to Fc RIIB in endothelium. Methods and Results: In cultured endothelial cells, Fc RI-blocking antibodies prevented CRP antagonism of eNOS, and CRP activated Src via Fc RI. CRP-induced increases in Fc RIIB immunoreceptor tyrosine-based inhibitory motif phosphorylation and SH2 domain-containing inositol 5 -phosphatase 1 activation were Srcdependent, 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 subunit of Fc RI (FcR / ) or Fc RIIB / mice. Whereas re-endothelialization was impaired in TG-CRP vs wild-type, it was normal in both FcR / ; TG-CRP and Fc RIIB / ; TG-CRP mice. Conclusions: CRP antagonism of eNOS is mediated by the coupling of Fc RI to Fc RIIB by Src kinase and resulting activation of SH2 domain-containing inositol 5 -phosphatase 1, and consistent with this mechanism, both Fc RI and Fc RIIB are required for CRP to blunt endothelial repair in vivo. Similar mechanisms underlie eNOS antagonism by immune complex. Fc RI and Fc RIIB may be novel therapeutic targets for preventing endothelial dysfunction in inflammatory or immune complex-mediated conditions. (Circ Res. 2011;109:1132-1140.)