Coupling of Fcγ receptor i to Fcγ receptor IIB by src kinase mediates c-reactive protein impairment of endothelial function

Nathan C. Sundgren, Weifei Zhu, Ivan S. Yuhanna, Ken L. Chambliss, Mohamed Ahmed, Keiji Tanigaki, Michihisa Umetani, Chieko Mineo, Philip W. Shaul

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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 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. Methods and 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.

Original languageEnglish (US)
Pages (from-to)1132-1140
Number of pages9
JournalCirculation Research
Volume109
Issue number10
DOIs
StatePublished - Oct 28 2011

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Fc Receptors
C-Reactive Protein
Nitric Oxide Synthase Type III
Proteins
src Homology Domains
Antigen-Antibody Complex
CSK tyrosine-protein kinase
Carotid Arteries
Endothelium
Tyrosine
IgG Receptors
Blocking Antibodies
src-Family Kinases

Keywords

  • C-reactive protein
  • endothelial nitric oxide synthase
  • Fc receptor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Coupling of Fcγ receptor i to Fcγ receptor IIB by src kinase mediates c-reactive protein impairment of endothelial function. / Sundgren, Nathan C.; Zhu, Weifei; Yuhanna, Ivan S.; Chambliss, Ken L.; Ahmed, Mohamed; Tanigaki, Keiji; Umetani, Michihisa; Mineo, Chieko; Shaul, Philip W.

In: Circulation Research, Vol. 109, No. 10, 28.10.2011, p. 1132-1140.

Research output: Contribution to journalArticle

Sundgren, Nathan C. ; Zhu, Weifei ; Yuhanna, Ivan S. ; Chambliss, Ken L. ; Ahmed, Mohamed ; Tanigaki, Keiji ; Umetani, Michihisa ; Mineo, Chieko ; Shaul, Philip W. / Coupling of Fcγ receptor i to Fcγ receptor IIB by src kinase mediates c-reactive protein impairment of endothelial function. In: Circulation Research. 2011 ; Vol. 109, No. 10. pp. 1132-1140.
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abstract = "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 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. Methods and 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.",
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T1 - Coupling of Fcγ receptor i to Fcγ receptor IIB by src kinase mediates c-reactive protein impairment of endothelial function

AU - Sundgren, Nathan C.

AU - Zhu, Weifei

AU - Yuhanna, Ivan S.

AU - Chambliss, Ken L.

AU - Ahmed, Mohamed

AU - Tanigaki, Keiji

AU - Umetani, Michihisa

AU - Mineo, Chieko

AU - Shaul, Philip W.

PY - 2011/10/28

Y1 - 2011/10/28

N2 - 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 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. Methods and 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.

AB - 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 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. Methods and 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.

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KW - endothelial nitric oxide synthase

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