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(Circulation Research. 2009;104:1275.)
© 2009 American Heart Association, Inc.

Molecular Medicine

C-Reactive Protein Inhibits Insulin Activation of Endothelial Nitric Oxide Synthase via the Immunoreceptor Tyrosine-Based Inhibition Motif of FcRIIB and SHIP-1

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

From the Division of Pulmonary and Vascular Biology (K.T., C.M., I.S.Y., K.L.C., P.W.S.), Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas; Diabetes Unit (M.J.Q.), National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Md; and Research Department (E.B.), MacroGenics Inc, Rockville, Md.

Correspondence to Chieko Mineo, Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390. E-mail Chieko.Mineo{at}utsouthwestern.edu

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 FcRIIB was demonstrated in vitro using blocking antibody, and reconstitution experiments with wild-type and mutant FcRIIB in NIH3T3^IR 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 FcRIIB 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.

Key Words: C-reactive protein • insulin • eNOS • FcRIIB • SHIP1

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