Skip to main content

Advertisement

SpringerLink
Log in

AGEs Decreased SIRT3 Expression and SIRT3 Activation Protected AGEs-Induced EPCs’ Dysfunction and Strengthened Anti-oxidant Capacity

  • ORIGINAL ARTICLE
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Advanced glycation end products (AGEs) have been confirmed to induce dysfunction in endothelial progenitor cells (EPCs) and play key roles in pathogenesis of diabetes-related vascular complications. The major function of sirtuin 3 (SIRT3) is to orchestrate oxidative metabolism and control reactive oxygen species (ROS) homeostasis, which are more closely related to EPCs’ dysfunction. Our study therefore was designed to explore the role of SIRT3 on AGEs-induced EPCs dysfunction of. EPCs isolated from healthy adults were stimulated with AGEs and the expression of SIRT3 was assessed. Then, EPCs transfected with ad-SIRT3 or siRNA-SIRT3 were cultured with or without AGEs. EPCs function, including proliferation, migration; expression of manganese superoxide dismutase (MnSOD), ROS production, and interleukin-8 (IL-8); and vascular endothelial growth factor (VEGF) production were measured. In some experiments, EPCs were pre-cultured with anti-receptor for advanced glycation end products (RAGE) antibody or anti-neutralizing antibody, and then proliferation, migration, expression of MnSOD, ROS production, and IL-8 and VEGF production were measured. Our results showed that SIRT3 expressed in EPCs and AGEs decreased SIRT3 expression. SIRT3 knockdown with siRNA-SIRT3 promoted dysfunction in EPCs whereas SIRT3 activation with ad-SIRT3 strengthened anti-oxidant capacity and protected AGE-impaired dysfunction. Moreover, RAGE may involve in AGEs-decreased SIRT3 expression in EPCs. These data suggested an important role of SIRT3 in regulating EPCs bioactivity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

REFERENCES

  1. Urbich, C., and S. Dimmeler. 2004. Endothelial progenitor cells: characterization and role in vascular biology. Circulation Research 95: 343–353.

    Article  CAS  PubMed  Google Scholar 

  2. Rabelink, T.J., H.C. de Boer, E.J. de Koning, and A.J. van Zonneveld. 2004. Endothelial progenitor cells: more than an inflammatory response. Arteriosclerosis, Thrombosis, and Vascular Biology (Dallas, TX) 24: 834–838.

    Article  CAS  Google Scholar 

  3. Groleau, J., S. Dussault, P. Haddad, J. Turgeon, C. Menard, J.S. Chan, and A. Rivard. 2010. Essential role of copper- zinc superoxide dismutase for ischemia-induced neovascularization via modulation of bone marrow-derived endothelial progenitor cells. Arteriosclerosis, Thrombosis, and Vascular Biology (Dallas, TX) 30: 2173–2181.

    Article  CAS  Google Scholar 

  4. Heller, G.V. 2005. Evaluation of the patient with diabetes mellitus and suspected coronary artery disease. The American Journal of Medicine 118: 9S–14S.

    PubMed  Google Scholar 

  5. Waltenberger, J. 2001. Impaired collateral vessel development in diabetes: potential cellular mechanisms and therapeutic implications. Cardiovascular Research 49: 554–560.

    Article  CAS  PubMed  Google Scholar 

  6. Palombo, C., M. Kozakova, C. Morizzo, L. Gnesi, M.C. Barsotti, P. Spontoni, F. Massart, P. Salvi, A. Balbarini, G. Saggese, et al. 2011. Circulating endothelial progenitor cells and large artery structure and function in young subjects with uncomplicated type 1 diabetes. Cardiovascular Diabetology 10: 88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tepper, O.M., R.D. Galiano, J.M. Capla, et al. 2002. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation 106:2781–6

  8. Vasa, M., S. Fichtlscherer, A. Aicher, et al. 2001. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circulation Research 89: E1–E7.

    Article  CAS  PubMed  Google Scholar 

  9. Jandeleit-Dahm, K., A. Watson, and A. Soro-Paavonen. 2008. The AGEs/RAGEs axis in diabetes-accelerated atherosclerosis. Clinical and Experimental Pharmacology and Physiology 35: 329–334.

    Article  CAS  PubMed  Google Scholar 

  10. Moriyama, T., M. Kemi, C. Okumura, K. Yoshihara, and T. Horie. 2010. Involvement of advanced glycation end-products, pentosidine and N(epsilon)-(carboxymethyl)lysine, in doxorubicin-induced cardiomyopathy in rats. Toxicology 268: 89–97.

    Article  CAS  PubMed  Google Scholar 

  11. Madonna, R., and R. de Caterina. 2011. Cellular and molecular mechanisms of vascular injury in diabetes—part II: cellular mechanisms and therapeutic targets. Vascular Pharmacology 54: 75–79.

    Article  CAS  PubMed  Google Scholar 

  12. Zhou, Y.J., H.W. Yang, X.G. Wang, and H. Zhang. 2009. Hepatocyte growth factor prevents advanced glycation end products-induced injury and oxidative stress through a PI3K/Akt-dependent pathway in human endothelial cells. Life Sciences 85: 670–677.

    Article  CAS  PubMed  Google Scholar 

  13. Chen, J., M. Song, S. Yu, P. Gao, Y. Yu, H. Wang, and L. Huang. 2010. Advanced glycation endproducts alter functions and promote apoptosis in endothelial progenitor cells through receptor for advanced glycation endproducts mediate overpression of cell oxidant stress. Molecular and Cellular Biochemistry 335: 137–146.

    Article  CAS  PubMed  Google Scholar 

  14. Li, H., X. Zhang, X. Guan, X. Cui, Y. Wang, H. Chu, and M. Cheng. 2012. Advanced glycation end products impair the migration, adhesion and secretion potentials of late endothelial progenitor cells. Cardiovascular Diabetology 11: 46.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Finkel, T., C.X. Deng, and R. Mostoslavsky. 2009. Recent progress in the biology and physiology of sirtuin. Nature 460: 587–591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Schwer, B., and E. Verdin. 2008. Conserved metabolic regulatory functions of sirtuins. Cell Metabolism 7: 104–112.

    Article  CAS  PubMed  Google Scholar 

  17. Lombard, D.B., F.W. Alt, H.L. Cheng, J. Bunkenborg, R.S. Streeper, R. Mostoslavsky, J. Kim, G. Yancopoulos, D. Valenzuela, A. Murphy, Y. Yang, Y. Chen, M.D. Hirschey, R.T. Bronson, M. Haigis, L.P. Guarente, R.V. Farese, S. Weissman, E. Verdin, and B. Schwer. 2007. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Molecular and Cellular Biology 27: 8807–8814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tseng, A.H., S.S. Shieh, and D.L. Wang. 2013. SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage. Free Radical Biology and Medicine 63: 222–234.

    Article  CAS  PubMed  Google Scholar 

  19. Sundaresan, N.R., M. Gupta, G. Kim, S.B. Rajamohan, A. Isbatan, and M.P. Gupta. 2009. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. Journal of Clinical Investigation 119: 2758–2771.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Hirschey, M.D., T. Shimazu, E. Jing, C.A. Grueter, A.M. Collins, B. Aouizerat, A. Stancakova, E. Goetzman, M.M. Lam, B. Schwer, R.D. Stevens, M.J. Muehlbauer, S. Kakar, N.M. Bass, J. Kuusisto, M. Laakso, F.W. Alt, C.B. Newgard, R.V. Farese Jr., C.R. Kahn, and E. Verdin. 2011. Sirt3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Molecular Cell 44: 177–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zeng, H., X. He, X. Hou, L. Li, and J.X. Chen. 2014. Apelin gene therapy increases myocardial vascular density and ameliorates diabetic cardiomyopathy via upregulation of sirtuin 3. American Journal of Physiology. Heart and Circulatory Physiology 306: 585–597.

    Article  Google Scholar 

  22. Cheng, C.C., S.J. Chang, Y.N. Chueh, T.S. Huang, P.H. Huang, S.M. Cheng, T.N. Tsai, J. Chen, and H.W. Wang. 2013. Distinct angiogenesis roles and surface markers of early and late endothelial progenitor cells revealed by functional group analyses. BMC Genomics 14: 182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hur, J., C.H. Yoon, H.S. Kim, J.H. Choi, H.J. Kang, K.K. Hwang, B.H. Oh, M.M. Lee, and Y.B. Park. 2004. Characterization of two types of endothelial progenitor cells and their different contributions to neovasculogenesis. Arteriosclerosis, Thrombosis, and Vascular Biology (Dallas, TX) 24: 288–293.

    Article  CAS  Google Scholar 

  24. Luo, X., Z. Yang, S. Zheng, Y. Cao, and Y. Wu. 2014. Sirt3 activation attenuated oxidized low-density lipoprotein-induced human umbilical vein endothelial cells’ apoptosis. Cell Biology International 24: 288–293.

    Google Scholar 

  25. Mortuza, R., S. Chen, B. Feng, S. Sen, and S. Chakrabarti. 2013. High glucose induced alteration of SIRTs in endothelial cells causes rapid aging in a p300 and FOXO regulated pathway. PloS One 8, e54514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shi, T., G.Q. Fan, and S.D. Xiao. 2010. SIRT3 reduces lipid accumulation in human hepatic cells via AMPK activation. Journal of Digestive Diseases 11: 55–62.

    Article  CAS  PubMed  Google Scholar 

  27. Chen, Y., J. Zhang, Y. Lin, Q. Lei, K.L. Guan, S. Zhao, and Y. Xiong. 2011. Tumour suppressor SIRT3 deacetylates and activates manganese superoxide dismutase to scavenge ROS. EMBO Reports 12: 534–541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Qiu, X., K. Brown, M.D. Hirschey, E. Verdin, and D. Chen. 2010. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metabolism 12: 662–667.

    Article  CAS  PubMed  Google Scholar 

  29. Ji, K.T., L. Qian, J.L. Nan, Y.J. Xue, S.Q. Zhang, G.Q. Wang, R.P. Yin, Y.J. Zhu, L.P. Wang, J. Ma, L.M. Liao, and J.F. Tang. 2015. Ox-LDL induces dysfunction of endothelial progenitor cells via activation of NF-kappaB. BioMed Research International 2015: 175291.

    PubMed  PubMed Central  Google Scholar 

  30. Someya, S., W. Yu, W.C. Hallows, J. Xu, J.M. Vann, C. Leeuwenburgh, M. Tanokura, J.M. Denu, and T.A. Prolla. 2010. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 143: 802–812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Iwaguro, H., J. Yamaguchi, C. Kalka, et al. 2002. Endothelial progenitor cell vascular endothelial growth factor gene transfer for vascular regeneration. Circulation 105: 732–738.

    Article  CAS  PubMed  Google Scholar 

  32. Kocher, A.A., M.D. Schuster, N. Bonaros, K. Lietz, G. Xiang, T.P. Martens, P.A. Kurlansky, H. Sondermeijer, P. Witkowski, A. Boyle, S. Homma, S.F. Wang, and S. Itescu. 2006. Myocardial homing and neovascularization by human bone marrow angioblasts is regulated by IL-8/Gro CXC chemokines. Journal of Molecular and Cellular Cardiology 40: 455–464.

    Article  CAS  PubMed  Google Scholar 

  33. Sun, C., C. Liang, Y. Ren, Y. Zhen, Z. He, H. Wang, H. Tan, X. Pan, and Z. Wu. 2009. Advanced glycation end products depress function of endothelial progenitor cells via p38 and ERK 1/2 mitogen-activated protein kinase pathways. Basic Research in Cardiology 104: 42–49.

    Article  CAS  PubMed  Google Scholar 

  34. Scheubel, R.J., S. Kahrstedt, H. Weber, J. Holtz, I. Friedrich, J. Borgermann, R.E. Silber, and A. Simm. 2006. Depression of progenitor cell function by advanced glycation endproducts (AGEs): potential relevance for impaired angiogenesis in advanced age and diabetes. Experimental Gerontology 41: 540–548.

    Article  CAS  PubMed  Google Scholar 

  35. Kawamura, Y., Y. Uchijima, N. Horike, K. Tonami, K. Nishiyama, T. Amano, T. Asano, Y. Kurihara, and H. Kurihara. 2010. SIRT3 protects in vitro-fertilized mouse preimplantation embryos against oxidative stress-induced p53-mediated developmental arrest. Journal of Clinical Investigation 120: 2817–2828.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Someya, S., W. Yu, W.C. Hallows, J. Xu, J.M. Vann, C. Leeuwenburgh, M. Tanokura, J.M. Denu, and T.A. Prolla. 2010. SIRT3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 143: 802–812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Neurobiology, Key Laboratory of Environment and Genes Related to Disease of Education Ministry, Xi’an Jiaotong University School of Medicine, Xi’an, Shaanxi, China

    Mingze Chang, Bei Zhang, Ye Tian, Ming Hu, Zhiqin Liu, Naibin Gu & Yong Liu

  2. Department of Neurology, Xi’an Central Hospital, Xi’an Jiaotong University School of Medicine, Xi’an, Shaanxi, China

    Mingze Chang, Gejuan Zhang, Zhengli Di & Xinlai Wang

Authors
  1. Mingze Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ye Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ming Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gejuan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhengli Di
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xinlai Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhiqin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Naibin Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yong Liu.

Ethics declarations

Conflict of Interest

All authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chang, M., Zhang, B., Tian, Y. et al. AGEs Decreased SIRT3 Expression and SIRT3 Activation Protected AGEs-Induced EPCs’ Dysfunction and Strengthened Anti-oxidant Capacity. Inflammation 40, 473–485 (2017). https://doi.org/10.1007/s10753-016-0493-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-016-0493-1

KEY WORDS

Search

Navigation