C-reactive protein inhibits insulin activation of endothelial nitric oxide synthase via the immunoreceptor tyrosine-based inhibition motif of FcγRIIB and SHIP-1

Keiji Tanigaki, Chieko Mineo, Ivan S. Yuhanna, Ken L. Chambliss, Michael J. Quon, Ezio Bonvini, Philip W. Shaul

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Insulin promotes the cardiovascular protective functions of the endothelium including NO production by endothelial NO synthase (eNOS), which it stimulates via Akt kinase which phosphorylates eNOS Ser1179. C-reactive protein (CRP) is an acute-phase reactant that is positively correlated with cardiovascular disease risk in patients with type 2 diabetes. We previously showed that CRP inhibits eNOS activation by insulin by blunting Ser1179 phosphorylation. We now elucidate the underlying molecular mechanisms. We first show in mice that CRP inhibits insulin-induced eNOS phosphorylation, indicating that these processes are operative in vivo. In endothelial cells we find that CRP attenuates insulin-induced Akt phosphorylation, and CRP antagonism of eNOS is negated by expression of constitutively active Akt; the inhibitory effect of CRP on Akt is also observed in vivo. A requirement for the IgG receptor FcγRIIB was demonstrated in vitro using blocking antibody, and reconstitution experiments with wild-type and mutant FcγRIIB in NIH3T3 cells revealed that these processes require the ITIM (immunoreceptor tyrosine-based inhibition motif) of the receptor. Furthermore, we find that endothelium express SHIP-1 (Src homology 2 domain-containing inositol 5′-phosphatase 1), that CRP induces SHIP-1 stimulatory phosphorylation in endothelium in culture and in vivo, and that SHIP-1 knockdown by small interfering RNA prevents CRP antagonism of insulin-induced eNOS activation. Thus, CRP inhibits eNOS stimulation by insulin via FcγRIIB and its ITIM, SHIP-1 activation, and resulting blunted activation of Akt. These findings provide mechanistic linkage among CRP, impaired insulin signaling in endothelium, and greater cardiovascular disease risk in type 2 diabetes.

Original languageEnglish (US)
Pages (from-to)1275-1282
Number of pages8
JournalCirculation research
Volume104
Issue number11
DOIs
StatePublished - Jun 5 2009

Keywords

  • C-reactive protein
  • ENOS
  • FcyRIIB
  • Insulin
  • SHIP1

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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