Skip to main content

Advertisement

SpringerLink
Log in

Exendin-4 reverses high glucose-induced endothelial progenitor cell dysfunction via SDF-1β/CXCR7–AMPK/p38-MAPK/IL-6 axis

  • Original Article
  • Published:
Acta Diabetologica Aims and scope Submit manuscript

Abstract

Aim

Exendin-4, a glucagon-like peptide-1 (GLP-1) analog, has been used for treating diabetes mellitus (DM). However, its effects on improving the dysfunction of high glucose (HG)-induced endothelial progenitor cells (EPCs) remain unclear. The present study explored the effects of Exendin-4 on improving dysfunction of EPCs and the underlying mechanism.

Methods

EPCs were isolated from SD rats and identified by flow cytometry. Next, the EPCs were treated by HG and high or low concentration of Exendin-4, and cell viability, migration and tube formation were, respectively, examined by performing MTT assay, wound-healing assay and tube formation assay. Interleukin-6 (IL-6) secretion was measured by enzyme-linked immunosorbent assay (ELISA). The protein expressions of relative stromal-derived growth factor-1β (SDF-1β), C-X-C chemokine receptor type 7 (CXCR7), AMP-activated protein kinase (AMPK), p38 and expressions of CXCR7 and IL-6 in EPCs were measured by Western blot. The cell behaviors of EPCs treated by HG and Exendin-4 with or without silencing of CXCR7 and IL-6 were detected.

Results

Exendin-4 reversed the inhibitory effects of HG on viability, migration and tube formation of EPCs and on SDF-1β/CXCR7–AMPK pathway in EPCs in a dose-dependent manner. Moreover, Exendin-4 promoted the effects of HG on IL-6 level in EPCs through the promotion of p38-MAPK phosphorylation and reduction of cleaved caspase-3 protein expressions in EPCs. However, silencing of CXCR7 and IL-6 reversed the effects of Exendin-4 on cell behaviors, inactivated SDF-1β/CXCR7–AMPK pathway and increased cleaved caspase-3 expression in EPCs.

Conclusions

Exendin-4 could ameliorate HG-induced EPC dysfunction through regulating the production of IL-6 via SDF-1β/CXCR7–AMPK/p38-MAPK axis.

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

Similar content being viewed by others

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Pippitt K, Li M, Gurgle HE (2016) Diabetes mellitus: screening and diagnosis. Am Fam Physician 93(2):103–109

    PubMed  Google Scholar 

  2. Lipska KJ, Krumholz H, Soones T, Lee SJ (2016) Polypharmacy in the aging patient: a review of glycemic control in older adults with type 2 diabetes. JAMA 315(10):1034–1045. https://doi.org/10.1001/jama.2016.0299

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Hinnen D (2017) Glucagon-like peptide 1 receptor agonists for type 2 diabetes. Diabetes Spectr 30(3):202–210. https://doi.org/10.2337/ds16-0026

    Article  PubMed  PubMed Central  Google Scholar 

  4. D'Alessio D (2016) Is GLP-1 a hormone: whether and when? J Diabetes Investig. https://doi.org/10.1111/jdi.12466

    Article  PubMed  PubMed Central  Google Scholar 

  5. Cao Y, Gao W, Jusko WJ (2012) Pharmacokinetic/pharmacodynamic modeling of GLP-1 in healthy rats. Pharm Res 29(4):1078–1086. https://doi.org/10.1007/s11095-011-0652-x

    Article  PubMed  CAS  Google Scholar 

  6. Jansen TJP, van Lith SAM, Boss M, Brom M, Joosten L, Béhé M, Buitinga M, Gotthardt M (2019) Exendin-4 analogs in insulinoma theranostics. J Labelled Comp Radiopharm 62(10):656–672. https://doi.org/10.1002/jlcr.3750

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Athauda D, Foltynie T (2018) Protective effects of the GLP-1 mimetic exendin-4 in Parkinson's disease. Neuropharmacology 136(Pt B):260–270. https://doi.org/10.1016/j.neuropharm.2017.09.023

    Article  PubMed  CAS  Google Scholar 

  8. Kang H-M, Sohn I, Jung J, Jeong J-W, Park C (2015) Exendin-4 protects hindlimb ischemic injury by inducing angiogenesis. Biochem Biophys Res Commun 465(4):758–763. https://doi.org/10.1016/j.bbrc.2015.08.080

    Article  PubMed  CAS  Google Scholar 

  9. Ventorp F, Bay-Richter C, Nagendra AS et al (2017) Exendin-4 Treatment Improves LPS-Induced Depressive-Like Behavior Without Affecting Pro-Inflammatory Cytokines. J Parkinsons Dis 7(2):263–273. https://doi.org/10.3233/JPD-171068

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Abdelwahed OM, Tork OM, Gamal El Din MM, Rashed L, Zickri M (2018) Effect of glucagon-like peptide-1 analogue; Exendin-4, on cognitive functions in type 2 diabetes mellitus; possible modulation of brain derived neurotrophic factor and brain Visfatin. Brain Res Bull 139:67–80. https://doi.org/10.1016/j.brainresbull.2018.02.002

    Article  PubMed  CAS  Google Scholar 

  11. Ozkok A, Yildiz A (2018) Endothelial progenitor cells and kidney diseases. Kidney Blood Press Res 43(3):701–718. https://doi.org/10.1159/000489745

    Article  PubMed  CAS  Google Scholar 

  12. Yao Y, Li Y, Song Q, Hu C, Xie W, Xu C, Chen Q, Wang QK (2019) Angiogenic factor AGGF1-primed endothelial progenitor cells repair vascular defect in diabetic mice. Diabetes 68(8):1635–1648. https://doi.org/10.2337/db18-1178

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Hu L, Dai S-C, Luan X, Chen J, Cannavicci A (2018) Dysfunction and therapeutic potential of endothelial progenitor cells in diabetes mellitus. J Clin Med Res 10(10):752–757. https://doi.org/10.14740/jocmr3581w

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Kadam S, Kanitkar M, Dixit K, Deshpande R, Seshadri V, Kale V (2018) Curcumin reverses diabetes-induced endothelial progenitor cell dysfunction by enhancing MnSOD expression and activity in vitro and in vivo. J Tissue Eng Regen Med 12(7):1594–1607. https://doi.org/10.1002/term.2684

    Article  PubMed  CAS  Google Scholar 

  15. Yang Y, Zhou Y, Wang Y et al (2020) Exendin-4 regulates endoplasmic reticulum stress to protect endothelial progenitor cells from high-glucose damage. Mol Cell Probes. https://doi.org/10.1016/j.mcp.2020.101527

    Article  PubMed  Google Scholar 

  16. Hu J, Wang S, Xiong Z et al (1864) Sun D (2018) Exosomal Mst1 transfer from cardiac microvascular endothelial cells to cardiomyocytes deteriorates diabetic cardiomyopathy. Biochim Biophys Acta Mol Basis Dis 11:3639–3649. https://doi.org/10.1016/j.bbadis.2018.08.026

    Article  CAS  Google Scholar 

  17. Qian N, Li X, Wang X, Wu C, Yin L, Zhi X (2018) Tryptase promotes breast cancer angiogenesis through PAR-2 mediated endothelial progenitor cell activation. Oncol Lett 16(2):1513–1520. https://doi.org/10.3892/ol.2018.8856

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Zhao Y, Tan Y, Xi S et al (2013) A novel mechanism by which SDF-1β protects cardiac cells from palmitate-induced endoplasmic reticulum stress and apoptosis via CXCR7 and AMPK/p38 MAPK-mediated interleukin-6 generation. Diabetes 62(7):2545–2558. https://doi.org/10.2337/db12-1233

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods (San Diego, Calif) 25(4):402–408. https://doi.org/10.1006/meth.2001.1262

    Article  CAS  Google Scholar 

  20. Bai C, Hou L, Zhang M, Pu Y, Guan W, Ma Y (2012) Characterization of vascular endothelial progenitor cells from chicken bone marrow. BMC Vet Res 8:54. https://doi.org/10.1186/1746-6148-8-54

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Rehman K, Akash MSH, Liaqat A, Kamal S, Qadir MI, Rasul A (2017) Role of Interleukin-6 in development of insulin resistance and type 2 diabetes mellitus. Crit Rev Eukaryot Gene Expr 27(3):229–236. https://doi.org/10.1615/CritRevEukaryotGeneExpr.2017019712

    Article  PubMed  Google Scholar 

  22. Li H, O'Meara M, Zhang X et al (2019) Ameliorating methylglyoxal-induced progenitor cell dysfunction for tissue repair in diabetes. Diabetes 68(6):1287–1302. https://doi.org/10.2337/db18-0933

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Berezin AE (2017) Endothelial progenitor cells dysfunction and impaired tissue reparation: The missed link in diabetes mellitus development. Diabetes Metab Syndr 11(3):215–220. https://doi.org/10.1016/j.dsx.2016.08.007

    Article  PubMed  Google Scholar 

  24. Chen S, Wang Z, Zhou H, He B, Hu D, Jiang H (2019) Icariin reduces high glucose-induced endothelial progenitor cell dysfunction via inhibiting the p38/CREB pathway and activating the Akt/eNOS/NO pathway. Exp Ther Med 18(6):4774–4780. https://doi.org/10.3892/etm.2019.8132

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Zeng Y-C, Peng L-S, Zou L et al (2017) Protective effect and mechanism of lycopene on endothelial progenitor cells (EPCs) from type 2 diabetes mellitus rats. Biomed Pharmacother 92:86–94. https://doi.org/10.1016/j.biopha.2017.05.018

    Article  PubMed  CAS  Google Scholar 

  26. Liu Z, Zhang M, Zhou T, Shen Q, Qin X (2018) Exendin-4 promotes the vascular smooth muscle cell re-differentiation through AMPK/SIRT1/FOXO3a signaling pathways. Atherosclerosis 276:58–66. https://doi.org/10.1016/j.atherosclerosis.2018.07.016

    Article  PubMed  CAS  Google Scholar 

  27. Hussien NI, Sorour SM, El-Kerdasy HI, Abdelrahman BA (2018) The glucagon-like peptide-1 receptor agonist Exendin-4, ameliorates contrast-induced nephropathy through suppression of oxidative stress, vascular dysfunction and apoptosis independent of glycaemia. Clin Exp Pharmacol Physiol 45(8):808–818. https://doi.org/10.1111/1440-1681.12944

    Article  PubMed  CAS  Google Scholar 

  28. Guo Z, Chen R, Zhang F, Ding M, Wang P (2018) Exendin-4 relieves the inhibitory effects of high glucose on the proliferation and osteoblastic differentiation of periodontal ligament stem cells. Arch Oral Biol. https://doi.org/10.1016/j.archoralbio.2018.03.014

    Article  PubMed  Google Scholar 

  29. Fallahi P, Corrado A, Di Domenicantonio A, Frenzilli G, Antonelli A, Ferrari SM (2016) CXCR3, CXCR5, CXCR6, and CXCR7 in Diabetes. Curr Drug Targets 17(5):515–519

    Article  CAS  Google Scholar 

  30. Hao H, Hu S, Chen H et al (2017) Loss of endothelial CXCR7 impairs vascular homeostasis and cardiac remodeling after myocardial infarction: implications for cardiovascular drug discovery. Circulation 135(13):1253–1264. https://doi.org/10.1161/CIRCULATIONAHA.116.023027

    Article  PubMed  CAS  Google Scholar 

  31. Tang Y, Liu J, Yan Y, Fang H, Guo C, Xie R, Liu Q (2018) 1,25-dihydroxyvitamin-D3 promotes neutrophil apoptosis in periodontitis with type 2 diabetes mellitus patients via the p38/MAPK pathway. Medicine (Baltimore) 97(52):e13903. https://doi.org/10.1097/MD.0000000000013903

    Article  CAS  Google Scholar 

  32. Tomita T (2010) Immunocytochemical localization of cleaved caspase-3 in pancreatic islets from type 1 diabetic subjects. Islets 2(1):24–29. https://doi.org/10.4161/isl.2.1.10041

    Article  PubMed  Google Scholar 

  33. Nakagami H, Morishita R, Yamamoto K et al (2001) Phosphorylation of p38 mitogen-activated protein kinase downstream of bax-caspase-3 pathway leads to cell death induced by high D-glucose in human endothelial cells. Diabetes 50(6):1472–1481

    Article  CAS  Google Scholar 

  34. Akbari M, Hassan-Zadeh V (2018) IL-6 signalling pathways and the development of type 2 diabetes. Inflammopharmacology 26(3):685–698. https://doi.org/10.1007/s10787-018-0458-0

    Article  PubMed  CAS  Google Scholar 

  35. Pedersen BK (2017) Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease. Eur J Clin Invest 47(8):600–611. https://doi.org/10.1111/eci.12781

    Article  PubMed  CAS  Google Scholar 

  36. Fan Y, Ye J, Shen F et al (2008) Interleukin-6 stimulates circulating blood-derived endothelial progenitor cell angiogenesis in vitro. J Cereb Blood Flow Metab 28(1):90–98. https://doi.org/10.1038/sj.jcbfm.9600509

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Not applicable.

Author information

Author notes

  1. Yong Yang and Yong Zhou authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiovascular Internal Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277, West Yanta Road, Xi’an, Shaanxi, China

    Yong Yang, Tingzhong Wang & Aiqun Ma

  2. Department of Cardiovascular Internal Medicine, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong, China

    Yong Yang & Xianglong Wei

  3. Department of Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong, China

    Yong Zhou

  4. Department of Cardiovascular Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China

    Yiyong Wang

  5. Department of Cardiovascular Medicine, University of Chinese Academy of Science Shenzhen Hospital, Shenzhen, Guangdong, China

    Lihao Wu

  6. Key Laboratory of Molecular Cardiology, Xi’an Jiaotong University, Xi’an, Shaanxi, China

    Tingzhong Wang & Aiqun Ma

  7. Key Laboratory of Environment and Genes Related To Diseases, Xi’an Jiaotong University, Xi’an, Shaanxi, China

    Tingzhong Wang & Aiqun Ma

Authors
  1. Yong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yong Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yiyong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xianglong Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lihao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tingzhong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aiqun Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YY and YZ substantially contributed to conception and design. YW and XW contributed to data acquisition. LW, TW and AM contributed to data analysis and interpretation. YY and YZ drafted the article or critically revised it for important intellectual content. All authors contributed to final approval of the version to be published. All authors contributed to the agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Aiqun Ma.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethics approval and consent to participate

All animal experiments were conducted following the guidelines of China Council on Animal Care and Use. This study has obtained approval from the Committee of Experimental Animals of The First Affiliated Hospital of Xi’an Jiaotong University (approval serial number: XNK20190806). No humans are involved in this study.

Consent for publication

Not applicable.

Additional information

Managed by Antonio Secchi.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PNG 70 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, Y., Zhou, Y., Wang, Y. et al. Exendin-4 reverses high glucose-induced endothelial progenitor cell dysfunction via SDF-1β/CXCR7–AMPK/p38-MAPK/IL-6 axis. Acta Diabetol 57, 1315–1326 (2020). https://doi.org/10.1007/s00592-020-01551-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00592-020-01551-3

Keywords

Search

Navigation