Coupling of Fc? receptor I to Fc? receptor IIb by SRC kinase mediates C-reactive protein impairment of endothelial function.

ABSTRACT: 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 domain-containing inositol 5'-phosphatase 1. In mice, CRP actions on eNOS blunt carotid artery re-endothelialization.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.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 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 ? 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.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.

SUBMITTER: Sundgren NC 

PROVIDER: S-EPMC3215097 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature