Coupling of Fc&ggr; Receptor I to Fc&ggr; 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&ggr; receptor IIB (Fc&ggr;RIIB), 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 Fc&ggr;RIIB in endothelium is not known. We determined the role of Fc&ggr; receptor I (Fc&ggr;RI) and the basis for coupling of Fc&ggr;RI to Fc&ggr;RIIB in endothelium. Methods and Results: In cultured endothelial cells, Fc&ggr;RI-blocking antibodies prevented CRP antagonism of eNOS, and CRP activated Src via Fc&ggr;RI. CRP-induced increases in Fc&ggr;RIIB 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 &ggr; subunit of Fc&ggr;RI (FcR&ggr;−/−) or Fc&ggr;RIIB−/− mice. Whereas re-endothelialization was impaired in TG-CRP vs wild-type, it was normal in both FcR&ggr;−/−; TG-CRP and Fc&ggr;RIIB−/−; TG-CRP mice. Conclusions: CRP antagonism of eNOS is mediated by the coupling of Fc&ggr;RI to Fc&ggr;RIIB by Src kinase and resulting activation of SH2 domain-containing inositol 5′-phosphatase 1, and consistent with this mechanism, both Fc&ggr;RI and Fc&ggr;RIIB are required for CRP to blunt endothelial repair in vivo. Similar mechanisms underlie eNOS antagonism by immune complex. Fc&ggr;RI and Fc&ggr;RIIB may be novel therapeutic targets for preventing endothelial dysfunction in inflammatory or immune complex-mediated conditions.

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