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C-Reactive Protein Suppresses Insulin Signaling in Endothelial Cells: Role of Spleen Tyrosine Kinase

Frontier Health Science (J.-W.X., K.I.), School of Human Environmental Science, Department of Pathophysiology (T.M.), School of Pharmaceutical Sciences, and Institute for World Health Development (Y.Y.), Mukogawa Women’s University, Nishinomiya 663-8179, Japan; and Section of Cellular Physiological Chemistry (I.M.), Graduate School, Tokyo Medical and Dental University, Tokyo 113-8549, Japan

Address all correspondence and requests for reprints to: Jin-Wen Xu, M.D., Ph.D., Frontier Health Science, School of Human Environmental Science, Mukogawa Women’s University, Nishinomiya, Hyogo 663-8179, Japan. E-mail: jwxu1001{at}yahoo.co.jp.

Although few epidemiological studies have demonstrated that C-reactive protein (CRP) is related to insulin resistance, no study to date has examined the molecular mechanism. Here, we show that recombinant CRP attenuates insulin signaling through the regulation of spleen tyrosine kinase (Syk) on small G-protein RhoA, jun N-terminal kinase (JNK) MAPK, insulin receptor substrate-1 (IRS-1), and endothelial nitric oxide synthase in vascular endothelial cells. Recombinant CRP suppressed insulin-induced NO production, inhibited the phosphorylation of Akt and endothelial nitric oxide synthase, and stimulated the phosphorylation of IRS-1 at the Ser307 site in a dose-dependent manner. These events were blocked by treatment with an inhibitor of RhoA-dependent kinase Y27632, or an inhibitor of JNK SP600125, or the transfection of dominant negative RhoA cDNA. Next, anti-CD64 Fc phagocytic receptor I (FcRI), but not anti-CD16 (FcRIIIa) or anti-CD32 (FcRII) antibody, partially blocked the recombinant CRP-induced phosphorylation of JNK and IRS-1 and restored, to a certain extent, the insulin-stimulated phosphorylation of Akt. Furthermore, we identified that recombinant CRP modulates the phosphorylation of Syk tyrosine kinase in endothelial cells. Piceatannol, an inhibitor of Syk tyrosine kinase, or infection of Syk small interference RNA blocked the recombinant CRP-induced RhoA activity and the phosphorylation of JNK and IRS-1. In addition, piceatannol also restrained CRP-induced endothelin-1 production. We conclude that recombinant CRP induces endothelial insulin resistance and dysfunction, and propose a new mechanism by which recombinant CRP induces the phosphorylation of JNK and IRS-1 at the Ser307 site through a Syk tyrosine kinase and RhoA-activation signaling pathway.

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