Effect of Candesartan Cilexetil as a Sensitive and Effective Inhibitor of SHP-1 on Insulin Signaling Pathway

doi:10.1007/s40242-013-2505-0

Chemical Research in Chinese Universities ›› 2013, Vol. 29 ›› Issue (4): 730-734.doi: 10.1007/s40242-013-2505-0

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Effect of Candesartan Cilexetil as a Sensitive and Effective Inhibitor of SHP-1 on Insulin Signaling Pathway

ZHANG Lei^1,3, ZHANG Shi-tao^1,3, ZHANG Xiao-ping², SUN Jing^1,3, WANG Yong-sen^1,3, LIU Yue-long^1,3, XUE Miao-miao^1,3, WANG Zhi¹, XING Shu^1,3, MA Jun-feng^1,3, LI Wan-nan^1,3, FU Xue-qi^1,3

1. Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education, Jilin University, Changchun 130012, P. R. China;
2. Clinical Laboratory, China-Japan Union Hospital, Jilin University, Changchun 130033, P. R. China;
3. State Engineering Laboratory of AIDS Vaccine, Jilin University, Changchun 130012, R. P. China

Received:2012-12-14 Revised:2013-01-30 Online:2013-08-01 Published:2013-07-15
Contact: LI Wan-nan, FU Xue-qi E-mail:liwannan@jlu.edu.cn;fxq@jlu.edu.cn
Supported by:
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).

Abstract

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.

Key words: SHP-1, Candesartan cilexetil, Inhibitor, Insulin sensitivity

ZHANG Lei, ZHANG Shi-tao, ZHANG Xiao-ping, SUN Jing, WANG Yong-sen, LIU Yue-long, XUE Miao-miao, WANG Zhi, XING Shu, MA Jun-feng, LI Wan-nan, FU Xue-qi. Effect of Candesartan Cilexetil as a Sensitive and Effective Inhibitor of SHP-1 on Insulin Signaling Pathway[J]. Chemical Research in Chinese Universities, 2013, 29(4): 730-734.

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Effect of Candesartan Cilexetil as a Sensitive and Effective Inhibitor of SHP-1 on Insulin Signaling Pathway

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