Abstract
The protein tyrosine phosphatases(PTPs) comprise a family of enzymes that specifically dephosphorylate tyrosyl residues. Among them, SHP-1 has been regarded as one of the best validated intracellular tyrosine phosphatases. Downregulation of SHP-1 has shown remarkable efficacy in improving insulin sensitivity in vivo in insulin signaling pathway. In this study, we found the role of Candesartan cilexetil targeting at SHP-1. The results indicate that Candesartan cilexetil was a competitive inhibitor to SHP-1(IC50=85.6 μmol/L and K i=24 μmol/L). We also found that Candesartan cilexetil was more sensitive towards SHP-1 compared with other PTPs. Through the consequence of Western blotting, it showed that Candesartan cilexetil can strengthen the level of tyrosine phosphorylation of several key cellular proteins[such as insulin receptor(IR), insulin receptor substrate(IRS) and ERK]_in insulin signaling pathway in HepG2 cells and improve the insulin sensitivity through inhibiting the protein phosphorylation of SHP-1. These findings showed that Candesartan cilexetil might be an important inhibitor of SHP-1 and had a great application potential in the treatment of diabetes through inhibiting the level of SHP-1 in insulin signaling pathway.
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Supported by the National Natural Science Foundation of China(Nos.81102859, 81000202, 31000358) and the Research Fund for the Doctoral Program of Higher Education of China(No.20090061110019).
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Zhang, L., Zhang, St., Zhang, Xp. et al. Effect of Candesartan cilexetil as a sensitive and effective inhibitor of SHP-1 on insulin signaling pathway. Chem. Res. Chin. Univ. 29, 730–734 (2013). https://doi.org/10.1007/s40242-013-2505-0
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DOI: https://doi.org/10.1007/s40242-013-2505-0