| First Author | Sundgren NC | Year | 2011 |
| Journal | Circ Res | Volume | 109 |
| Issue | 10 | Pages | 1132-40 |
| PubMed ID | 21940940 | Mgi Jnum | J:188820 |
| Mgi Id | MGI:5442265 | Doi | 10.1161/CIRCRESAHA.111.254573 |
| Citation | Sundgren NC, et al. (2011) Coupling of Fcgamma receptor I to Fcgamma receptor IIb by SRC kinase mediates C-reactive protein impairment of endothelial function. Circ Res 109(10):1132-40 |
| abstractText | 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 Fcgamma receptor IIB (FcgammaRIIB), 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 FcgammaRIIB in endothelium is not known. We determined the role of Fcgamma receptor I (FcgammaRI) and the basis for coupling of FcgammaRI to FcgammaRIIB in endothelium. METHODS AND RESULTS: In cultured endothelial cells, FcgammaRI-blocking antibodies prevented CRP antagonism of eNOS, and CRP activated Src via FcgammaRI. CRP-induced increases in FcgammaRIIB 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 gamma subunit of FcgammaRI (FcRgamma(-/-)) or FcgammaRIIB(-/-) mice. Whereas re-endothelialization was impaired in TG-CRP vs wild-type, it was normal in both FcRgamma(-/-); TG-CRP and FcgammaRIIB(-/-); TG-CRP mice. CONCLUSIONS: CRP antagonism of eNOS is mediated by the coupling of FcgammaRI to FcgammaRIIB by Src kinase and resulting activation of SH2 domain-containing inositol 5'-phosphatase 1, and consistent with this mechanism, both FcgammaRI and FcgammaRIIB are required for CRP to blunt endothelial repair in vivo. Similar mechanisms underlie eNOS antagonism by immune complex. FcgammaRI and FcgammaRIIB may be novel therapeutic targets for preventing endothelial dysfunction in inflammatory or immune complex-mediated conditions. |
