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Advanced glycation end products depress function of endothelial progenitor cells via p38 and ERK 1/2 mitogen-activated protein kinase pathways

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Abstract

Objective

Advanced glycation end products (AGEs) and endothelial progenitor cells (EPCs) play divergent roles in the process of atherosclerosis. We investigated the effects of AGE-human serum albumin (AGE-HSA) on receptor expression for AGEs (RAGE) and EPCs apoptosis.

Methods

The human mononuclear cells were obtained by Ficoll density gradient centrifugation and cultured in M199 medium containing rh-VEGF (30 ng/ml), rh-b-FGF(6 ng/ml) and 20% NBCS for 8 days. The adhesive EPCs were sequentially harvested after 24 h synchronization and challenged with AGE-HSA (concentration range from 0 to 300 µg/ml) for 24 h and 200 µg/ml AGE-HSA (time range from 0 to 36 h). EPCs apoptosis and migration were determined, expressions of RAGE, phosphorylated ERK1/2, JNK and p38 mitogen-activated protein kinase (MAPK) of EPCs were quantified by fluorescent quantitation RT-PCR and Western-blot, effect of AGE-HSA on NF-κB activtiy was determined by EMSA (electrophoretic mobility shift assay) in the presence and absence of special MAPK pathways pathway inhibitors.

Results

AGE-HSA upregulated the expression of RAGE, this effect could be significantly inhibited by p38 MAPK and ERK MAPK inhibitor, but not by JNK MAPK inhibitor. AGE-HSA also promoted EPCs apoptosis and inhibited EPCs migration and increased NF-κB activity, these effects could be significantly attenuated by the anti-RAGE neutralizing antibody as well as by p38 and ERK MAPK inhibitors.

Conclusion

AGE-HSA could promote atherosclerosis by upregulating EPCs RAGE expressions and promoting EPCs apoptosis via p38, ERK MAPK pathways, activation of NF-κB might also play a role in this process.

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Acknowledgments

This work was supported by Major National Basic Research Development Program of People’s Republic of China (2005CB523309). We thank Jack Williams for the help in the preparation of this manuscript.

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Authors and Affiliations

  1. Dept. of Cardiology, 2nd Hospital Affiliated to the Second Military Medical University, Shanghai, People’s Republic of China

    Chengbo Sun, Chun Liang, Yusheng Ren, Yi Zhen, Zhiqing He, Hua Wang, Hongbing Tan, Xiaoming Pan &  Zonggui Wu

  2. Department of Cardiology, First people’s Hospital of Lianyungang City, Lianyungang, Jiangsu Province, People’s Republic of China

    Chengbo Sun

  3. Dept. of Cardiology, Changzheng Hospital, 415 Fengyang Road, Shanghai, 200003, People’s Republic of China

    Zonggui Wu

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  1. Chengbo Sun
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Correspondence to Zonggui Wu.

Additional information

C. Sun and C. Liang contributed equally to this work.

Returned for 1. Revision: 13 December 2007 1. Revision received: 20 February 2008 Returned for 2. Revision: 7 March 2008 2. Revision received: 9 June 2008

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Sun, C., Liang, C., Ren, Y. et al. Advanced glycation end products depress function of endothelial progenitor cells via p38 and ERK 1/2 mitogen-activated protein kinase pathways. Basic Res Cardiol 104, 42–49 (2009). https://doi.org/10.1007/s00395-008-0738-8

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