Skip to main content
SpringerLink
Log in

Advanced glycation end-products induce heparanase expression in endothelial cells by the receptor for advanced glycation end products and through activation of the FOXO4 transcription factor

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

As an endo-β (1-4)-d-glucuronidase, heparanase can specifically cleave carbohydrate chains of heparan sulfate (HS) and has been implicated in development of endothelial cells dsyfunction. The advanced glycation end products (AGEs) play a pivotal role in the pathology of diabetic complications. In the present study, we investigated the effect of AGE-bovine serum albumin (AGE-BSA) on heparanase expression in human microvascular endothelial cells (HMVECs) and the underlying molecular mechanisms. The results indicated that in vitro direct exposure of HMVECs to AGE-BSA (300, 1000, and 3000 μg/ml) could increase heparanase mRNA and protein expression in a dose and time-dependent manner. The effect of 1000 μg/ml AGE-BSA could be abolished by neutralization with antibody of the receptor for advanced glycation end products (RAGE). Moreover, pretreatment with inhibitors of nuclear factor-κB (NF-κB) or PI3-kinase did not affect heparanase expression induced by AGE-BSA. Nevertheless, small interference RNA (siRNA) for transcriptional factor FOXO4 could reduce the increase of heparanase expression in HMVECs induced by 1000 μg/ml AGE-BSA. These results suggest that AGEs could induce heparanase expression in HMVECs by RAGE and predominantly through activation of the FOXO4 transcription factor.

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

Similar content being viewed by others

References

  1. Vlodavsky I, Ilan N, Naggi A, Casu B (2007) Heparanase: structure, biological functions, and inhibition by heparin-derived mimetics of heparan sulfate. Curr Pharm Des 13:2057–2073

    Article  CAS  PubMed  Google Scholar 

  2. Vlodavsky I, Friedmann Y (2001) Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis. J Clin Investig 108:341–347

    CAS  PubMed  Google Scholar 

  3. Baker AB, Chatzizisis YS, Beigel R, Jonas M, Stone BV, Coskun AU, Maynard C, Rogers C, Koskinas KC, Feldman CL, Stone PH, Edelman ER (2010) Regulation of heparanase expression in coronary artery disease in diabetic, hyperlipidemic swine. Atherosclerosis 213:436–442

    Article  CAS  PubMed  Google Scholar 

  4. Wijnhoven TJ, van den Hoven MJ, Ding H, van Kuppevelt TH, van der Vlag J, Berden JH, Prinz RA, Lewis EJ, Schwartz M, Xu X (2008) Heparanase induces a differential loss of heparan sulphate domains in overt diabetic nephropathy. Diabetologia 51:372–382

    Article  CAS  PubMed  Google Scholar 

  5. Katz A, Van-Dijk DJ, Aingorn H, Erman A, Davies M, Darmon D, Hurvitz H, Vlodavsky I (2002) Involvement of human heparanase in the pathogenesis of diabetic nephropathy. Isr Med Assoc J 4:996–1002

    CAS  PubMed  Google Scholar 

  6. van den Hoven MJ, Rops AL, Bakker MA, Aten J, Rutjes N, Roestenberg P, Goldschmeding R, Zcharia E, Vlodavsky I, van der Vlag J, Berden JH (2006) Increased expression of heparanase in overt diabetic nephropathy. Kidney Int 70:2100–2108

    PubMed  Google Scholar 

  7. Maxhimer JB, Somenek M, Rao G, Pesce CE, Baldwin D Jr, Gattuso P, Schwartz MM, Lewis EJ, Prinz RA, Xu X (2005) Heparanase-1 gene expression and regulation by high glucose in renal epithelial cells: a potential role in the pathogenesis of proteinuria in diabetic patients. Diabetes 54:2172–2178

    Article  CAS  PubMed  Google Scholar 

  8. Fukami K, Yamagishi S, Ueda S, Okuda S (2008) Role of AGEs in diabetic nephropathy. Curr Pharm Des 14:946–952

    Article  CAS  PubMed  Google Scholar 

  9. Jandeleit-Dahm K, Watson A, Soro-Paavonen A (2008) The AGE/RAGE axis in diabetes-accelerated atherosclerosis. Clin Exp Pharmacol Physiol 35:329–334

    Article  CAS  PubMed  Google Scholar 

  10. Yamagishi S, Nakamura K, Matsui T, Noda Y, Imaizumi T (2008) Receptor for advanced glycation end products (RAGE): a novel therapeutic target for diabetic vascular complication. Curr Pharm Des 14:487–495

    Article  CAS  PubMed  Google Scholar 

  11. Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC, Elliston K, Stern D, Shaw A (1992) Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem 267:14998–15004

    CAS  PubMed  Google Scholar 

  12. Soulis T, Thallas V, Youssef S, Gilbert RE, McWilliam BG, Murray-McIntosh RP, Cooper ME (1997) Advanced glycation end products and their receptors co-localise in rat organs susceptible to diabetic microvascular injury. Diabetologia 40:619–628

    Article  CAS  PubMed  Google Scholar 

  13. Wendt T, Tanji N, Guo J, Hudson BI, Bierhaus A, Ramasamy R, Arnold B, Nawroth PP, Yan SF, D’Agati V, Schmidt AM (2003) Glucose, glycation, and RAGE: implications for amplification of cellular dysfunction in diabetic nephropathy. J Am Soc Nephrol 14:1383–1395

    Article  CAS  PubMed  Google Scholar 

  14. Lewis EJ, Xu X (2008) Abnormal glomerular permeability characteristics in diabetic nephropathy: implications for the therapeutic use of low-molecular weight heparin. Diabetes Care 31:202–207

    Article  Google Scholar 

  15. Wang F, Wang Y, Kim MS, Puthanveetil P, Ghosh S, Luciani DS, Johnson JD, Abrahani A, Rodrigues B (2010) Glucose-induced endothelial heparanase secretion requires cortical and stress actin reorganization. Cardiovasc Res 87:127–136

    Article  CAS  PubMed  Google Scholar 

  16. Han J, Mandal AK, Hiebert LM (2005) Endothelial cell injury by high glucose and heparanase is prevented by insulin, heparin and basic fibroblast growth factor. Cardiovasc Diabetol 4:12

    Article  PubMed  Google Scholar 

  17. Jakus V, Rietbrock N (2004) Advanced glycation end-products and the progress of diabetic vascular complications. Physiol Res 53:131–142

    CAS  PubMed  Google Scholar 

  18. Zhou G, Li C, Cai L (2004) Advanced glycation end-products induce connective tissue growth factor-mediated renal fibrosis predominantly through transforming growth factor beta-independent pathway. Am J Pathol 165:2033–2043

    Article  CAS  PubMed  Google Scholar 

  19. Chen G, Wang D, Vikramadithyan R, Yagyu H, Saxena U, Pillarisetti S, Goldberg IJ (2004) Inflammatory cytokines and fatty acids regulate endothelial cell heparanase expression. Biochemistry 43:4971–4977

    Article  CAS  PubMed  Google Scholar 

  20. Vlodavsky I, Friedmann Y, Elkin M, Aingorn H, Atzmon R, Ishai-Michaeli R, Bitan M, Pappo O, Peretz T, Michal I, Spector L, Pecker I (1999) Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis. Nat Med 5:793–802

    Article  CAS  PubMed  Google Scholar 

  21. Vreys V, Delande N, Zhang Z, Coomans C, Roebroek A, Dürr J, David G (2005) Cellular uptake of mammalian heparanase precursor involves low density lipoprotein receptor-related proteins, mannose 6-phosphate receptors, and heparan sulfate proteoglycans. J Biol Chem 280:33141–33148

    Article  CAS  PubMed  Google Scholar 

  22. Ilan N, Elkin M, Vlodavsky I (2006) Regulation, function and clinical significance of heparanase in cancer metastasis and angiogenesis. Int J Biochem Cell Biol 38:2018–2039

    Article  CAS  PubMed  Google Scholar 

  23. Hulett MD, Hornby JR, Ohms SJ, Zuegg J, Freeman C, Gready JE, Parish CR (2000) Identification of active-site residues of the pro-metastatic endoglycosidase heparanase. Biochemistry 39:15659–15667

    Article  CAS  PubMed  Google Scholar 

  24. Baker AB, Groothuis A, Jonas M, Ettenson DS, Shazly T, Zcharia E, Vlodavsky I, Seifert P, Edelman ER (2009) Heparanase alters arterial structure, mechanics, and repair following endovascular stenting in mice. Circ Res 104:380–387

    Article  CAS  PubMed  Google Scholar 

  25. Han J, Woytowich AE, Mandal AK, Hiebert LM (2007) Heparanase upregulation in high glucose-treated endothelial cells is prevented by insulin and heparin. Exp Biol Med (Maywood) 232:927–934

    CAS  Google Scholar 

  26. Sakata N, Imanaga Y, Meng J, Tachikawa Y, Takebayashi S, Nagai R, Horiuchi S (1999) Increased advanced glycation end products in atherosclerotic lesions of patients with end-stage renal disease. Atherosclerosis 142:67–77

    Article  CAS  PubMed  Google Scholar 

  27. Goldin A, Beckman JA, Schmidt AM, Creager MA (2006) Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation 114:597–605

    Article  CAS  PubMed  Google Scholar 

  28. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820

    Article  CAS  PubMed  Google Scholar 

  29. Tanikawa T, Okada Y, Tanikawa R, Tanaka Y (2009) Advanced glycation end products induce calcification of vascular smooth muscle cells through RAGE/p38 MAPK. J Vasc Res 46:572–580

    Article  CAS  PubMed  Google Scholar 

  30. Wautier MP, Chappey O, Corda S, Stern DM, Schmidt AM, Wautier JL (2001) Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am J Physiol Endocrinol Metab 280:685–694

    Google Scholar 

  31. Liu Y, Liang C, Liu X, Liao B, Pan X, Ren Y, Fan M, Li M, He Z, Wu J, Wu Z (2010) AGEs increased migration and inflammatory responses of adventitial fibroblasts via RAGE, MAPK and NF-kappaB pathways. Atherosclerosis 208:34–42

    Article  CAS  PubMed  Google Scholar 

  32. Furukawa-Hibi Y, Kobayashi Y, Chen C, Motoyama N (2005) FOXO transcription factors in cell-cycle regulation and the response to oxidative stress. Antioxid Redox Signal 7:752–760

    Article  CAS  PubMed  Google Scholar 

  33. Chuang PY, Yu Q, Fang W, Uribarri J, He JC (2007) Advanced glycation endproducts induce podocyte apoptosis by activation of the FOXO4 transcription factor. Kidney Int 72:965–976

    Article  CAS  PubMed  Google Scholar 

  34. Turgut F, Bolton WK (2010) Potential new therapeutic agents for diabetic kidney disease. Am J Kidney Dis 55:928–940

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

This work was supported by the Nature Scientific Foundation of Jiangsu Province (No.BK2008490 and BK2010595).

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, 155 Han-Zhong Road, Nanjing, 210029, China

    Xiao-Fei An, Lei Zhou, Peng-Jun Jiang, Shi-Chao Ten & Jiang-Yi Yu

  2. National Drug Screen Laboratory, China Pharmaceutical University, Nanjing, 210009, China

    Ming Yan

  3. Department of Neurology, Philippusstift Hospital, Essen, 45355, Germany

    Yu-Jun Huang

  4. Department of Bone Molecular Biology, The Second Military University, 174 Chang-Hai Road, Shanghai, 200433, China

    Su-Na Zhang & Yun-Fei Niu

Authors
  1. Xiao-Fei An
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lei Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peng-Jun Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ming Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yu-Jun Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Su-Na Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yun-Fei Niu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shi-Chao Ten
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jiang-Yi Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yun-Fei Niu or Jiang-Yi Yu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

An, XF., Zhou, L., Jiang, PJ. et al. Advanced glycation end-products induce heparanase expression in endothelial cells by the receptor for advanced glycation end products and through activation of the FOXO4 transcription factor. Mol Cell Biochem 354, 47–55 (2011). https://doi.org/10.1007/s11010-011-0804-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-011-0804-7

Keywords

Search

Navigation