Effect of Candesartan Cilexetil as a Sensitive and Effective Inhibitor of SHP-1 on Insulin Signaling Pathway |
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Authors: | 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 |
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Institution: | 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 |
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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 Ki=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 proteinssuch 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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Keywords: | SHP-1 Candesartan cilexetil Inhibitor Insulin sensitivity |
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