Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Soluble receptor for advanced glycation end-products independently influences individual age-dependent increase of arterial stiffness

Hypertension Research volume 43, pages 111–120 (2020)Cite this article

Abstract

Circulating levels of soluble receptor for advanced glycation end-products (sRAGE) have been suggested to have a protective role in neutralizing advanced glycation end-products (AGEs) and their pathological effects on vessel walls. We aimed to investigate the association between the circulating concentration of sRAGE and the dynamics of arterial wall stiffening as a manifestation of vascular aging in the general population. In a prospective cohort study, we longitudinally followed 530 general-population-based subjects (subsample of Czech post-MONICA study). Aortic pulse wave velocity (PWV) was measured twice (at baseline and after ~8 years of follow-up) using a SphygmoCor device (AtCor Medical Ltd), and the intraindividual change in PWV per year (∆PWV/year) was calculated. Concentrations of sRAGE were assessed at baseline by ELISA (R&D Systems). The average ∆PWV/year significantly decreased across the sRAGE quintiles (p = 0.048), and a drop by one sRAGE quintile was associated with an ~21% increase in the relative risk of accelerated age-dependent stiffening (∆PWV/year ≥ 0.2 m/s). Subjects in the bottom quintile of sRAGE (<889.74 pg/mL) had a fully adjusted odds ratio of accelerated stiffening of 1.72 (95% CI: 1.06–2.79), p = 0.028, while those with high sRAGE concentrations (≥1695.2 pg/mL) showed the opposite effect [odds ratio 0.55 (95% CI: 0.33–0.90), p = 0.017]. In conclusion, the circulating status of sRAGE independently influenced the individual progression of arterial stiffness over time. This finding strongly supports the hypothesis that high sRAGE has a protective role against vascular aging.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

Similar content being viewed by others

References

  1. O’Rourke MF, Mancia G. Arterial stiffness. J Hypertens. 1999;17:1–4.

    PubMed  Google Scholar 

  2. Dao HH, Essalihi R, Bouvet C, Moreau P. Evolution and modulation of age-related medial elastocalcinosis: impact on large artery stiffness and isolated systolic hypertension. Cardiovasc Res. 2005;66:307–17.

    CAS  PubMed  Google Scholar 

  3. Robert L. Aging of the vascular-wall and atherosclerosis. Exp Gerontol. 1999;34:491–501.

    CAS  PubMed  Google Scholar 

  4. Folkow B, Svanborg A. Physiology of cardiovascular aging. Physiol Rev. 1993;73:725–64.

    CAS  PubMed  Google Scholar 

  5. Collaboration TRVfAS. Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: ‘establishing normal and reference values’. Eur Heart J. 2010;31:2338–50.

    Google Scholar 

  6. Cecelja M, Chowienczyk P. Dissociation of aortic pulse wave velocity with risk factors for cardiovascular disease other than hypertension: a systematic review. Hypertension. 2009;54:1328–36.

    CAS  PubMed  Google Scholar 

  7. McEniery CM, Yasmin, Hall IR, Qasem A, Wilkinson IB, Cockcroft JR. Normal vascular aging: differential effects on wave reflection and aortic pulse wave velocity: the Anglo-Cardiff Collaborative Trial (ACCT). J Am Coll Cardiol. 2005;46:1753–60.

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  9. Schleicher ED, Wagner E, Nerlich AG. Increased accumulation of the glycoxidation product N(epsilon)-(carboxymethyl)lysine in human tissues in diabetes and aging. J Clin Investig. 1997;99:457–68.

    CAS  PubMed  Google Scholar 

  10. Kalousova M, Zima T, Tesar V, Dusilova-Sulkova S, Skrha J. Advanced glycoxidation end products in chronic diseases-clinical chemistry and genetic background. Mutat Res. 2005;579:37–46.

    CAS  PubMed  Google Scholar 

  11. Basta G. Receptor for advanced glycation endproducts and atherosclerosis: from basic mechanisms to clinical implications. Atherosclerosis. 2008;196:9–21.

    CAS  PubMed  Google Scholar 

  12. Georgianos PI, Pikilidou MI, Liakopoulos V, Balaskas EV, Zebekakis PE. Arterial stiffness in end-stage renal disease-pathogenesis, clinical epidemiology, and therapeutic potentials. Hypertens Res. 2018;41:309–19.

    PubMed  Google Scholar 

  13. Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YCE, et al. Cloning and expression of a cell-surface receptor for advanced glycosylation end-products of proteins. J Biol Chem. 1992;267:14998–5004.

    CAS  PubMed  Google Scholar 

  14. Schnider SL, Kohn RR. Effects of age and diabetes mellitus on the solubility and nonenzymatic glucosylation of human skin collagen. J Clin Investig. 1981;67:1630–5.

    CAS  PubMed  Google Scholar 

  15. Vasan S, Zhang X, Kapurniotu A, Bernhagen J, Teichberg S, Basgen J, et al. An agent cleaving glucose-derived protein crosslinks in vitro and in vivo. Nature. 1996;382:275–8.

    CAS  PubMed  Google Scholar 

  16. Koyama H, Yamamoto H, Nishizawa Y. RAGE and soluble RAGE: potential therapeutic targets for cardiovascular diseases. Mol Med. 2007;13:625–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Park L, Raman KG, Lee KJ, Lu Y, Ferran JrLJ, Chow WS, et al. Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts. Nat Med. 1998;4:1025.

    CAS  PubMed  Google Scholar 

  18. Basta G, Corciu AI, Vianello A, Del Turco S, Foffa I, Navarra T, et al. Circulating soluble receptor for advanced glycation end-product levels are decreased in patients with calcific aortic valve stenosis. Atherosclerosis. 2010;210:614–8.

    CAS  PubMed  Google Scholar 

  19. Koyama H, Shoji T, Yokoyama H, Motoyama K, Mori K, Fukumoto S, et al. Plasma level of endogenous secretory RAGE is associated with components of the metabolic syndrome and atherosclerosis. Arterioscler Thromb Vasc Biol. 2005;25:2587–93.

    CAS  PubMed  Google Scholar 

  20. Mayer O, Seidlerova J, Filipovsky J, Vagovicova P, Wohlfahrt P, Cifkova R, et al. Soluble receptor for advanced glycation end products and increased aortic stiffness in the general population. Hypertens Res. 2016;39:266–71.

    CAS  PubMed  Google Scholar 

  21. Falcone C, Emanuele E, D’Angelo A, Buzzi MP, Belvito C, Cuccia M, et al. Plasma levels of soluble receptor for advanced glycation end products and coronary artery disease in nondiabetic men. Arterioscler Thromb Vasc Biol. 2005;25:1032–7.

    CAS  PubMed  Google Scholar 

  22. Cifkova R, Skodova Z, Bruthans J, Adamkova V, Jozifova M, Galovcova M, et al. Longitudinal trends in major cardiovascular risk factors in the Czech population between 1985 and 2007/8. Czech MONICA and Czech post-MONICA. Atherosclerosis. 2010;211:676–81.

    CAS  PubMed  Google Scholar 

  23. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J. 2006;27:2588–605.

    PubMed  Google Scholar 

  24. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis. 2016;252:207–74.

    CAS  PubMed  Google Scholar 

  25. Herbert A, Cruickshank JK, Laurent S, Boutouyrie P. Establishing reference values for central blood pressure and its amplification in a general healthy population and according to cardiovascular risk factors. Eur Heart J. 2014;35:3122–33.

    CAS  PubMed  Google Scholar 

  26. Nichols M, Townsend N, Scarborough P, Rayner M. Cardiovascular disease in Europe 2014: epidemiological update. Eur Heart J. 2014;35:2950–9.

    CAS  PubMed  Google Scholar 

  27. Dimitriadis K, Tsioufis C, Kasiakogias A, Miliou A, Poulakis M, Kintis K, et al. Soluble receptor for advanced glycation end-product levels are related to albuminuria and arterial stiffness in essential hypertension. Nutr Metab Cardiovasc Dis. 2013;23:382–8.

    CAS  PubMed  Google Scholar 

  28. Geroldi D, Falcone C, Emanuele E, D’Angelo A, Calcagnino M, Buzzi MP, et al. Decreased plasma levels of soluble receptor for advanced glycation end-products in patients with essential hypertension. J Hypertens. 2005;23:1725–9.

    CAS  PubMed  Google Scholar 

  29. McNulty M, Mahmud A, Feely J. Advanced glycation end-products and arterial stiffness in hypertension. Am J Hypertens. 2007;20:242–7.

    CAS  PubMed  Google Scholar 

  30. Semba RD, Najjar SS, Sun K, Lakatta EG, Ferrucci L. Serum carboxymethyl-lysine, an advanced glycation end product, is associated with increased aortic pulse wave velocity in adults. Am J Hypertens. 2009;22:74–9.

    CAS  PubMed  Google Scholar 

  31. Miranda ER, Somal VS, Mey JT, Blackburn BK, Wang E, Farabi S, et al. Circulating soluble RAGE isoforms are attenuated in obese, impaired-glucose-tolerant individuals and are associated with the development of type 2 diabetes. Am J Physiol Endocrinol Metab. 2017;313:E631–e640.

    PubMed  PubMed Central  Google Scholar 

  32. Yoon SJ, Park S, Park C, Chang W, Cho DK, Ko YG, et al. Association of soluble receptor for advanced glycation end-product with increasing central aortic stiffness in hypertensive patients. Coron Artery Dis. 2012;23:85–90.

    PubMed  Google Scholar 

  33. Dozio E, Ambrogi F, de Cal M, Vianello E, Ronco C, Corsi Romanelli MM. Role of the soluble receptor for advanced glycation end products (sRAGE) as a prognostic factor for mortality in hemodialysis and peritoneal dialysis patients. Mediators Inflamm. 2018;2018:1347432.

    PubMed  PubMed Central  Google Scholar 

  34. Jabaudon M, Blondonnet R, Pereira B, Cartin-Ceba R, Lichtenstern C, Mauri T, et al. Plasma sRAGE is independently associated with increased mortality in ARDS: a meta-analysis of individual patient data. Intensive Care Med. 2018;44:1388–99.

    PubMed  PubMed Central  Google Scholar 

  35. Paradela-Dobarro B, Fernandez-Trasancos A, Bou-Teen D, Eiras S, Gonzalez-Ferreiro R, Agra RM, et al. Evolution and bad prognostic value of advanced glycation end products after acute heart failure: relation with body composition. Cardiovasc Diabetol. 2017;16:115.

    PubMed  PubMed Central  Google Scholar 

  36. Rodriguez-Ruiz E, Lopez-Lago A, Hernandez-Vaquero R, Granja-Gomez I, Estany-Gestal A, Alvarez E, et al. First-days reduction of plasma and skin advanced glycation end products is related to outcome in septic patients. Shock. 2019. https://doi.org/10.1097/SHK.0000000000001396 [Epub ahead of print].

  37. Grauen Larsen H, Yndigegn T, Marinkovic G, Grufman H, Mares R, Nilsson J, et al. The soluble receptor for advanced glycation end-products (sRAGE) has a dual phase-dependent association with residual cardiovascular risk after an acute coronary event. Atherosclerosis. 2019;287:16–23.

    CAS  PubMed  Google Scholar 

  38. Reichert S, Triebert U, Santos AN, Hofmann B, Schaller HG, Schlitt A, et al. Soluble form of receptor for advanced glycation end products and incidence of new cardiovascular events among patients with cardiovascular disease. Atherosclerosis. 2017;266:234–9.

    CAS  PubMed  Google Scholar 

  39. Jensen LJ, Flyvbjerg A, Bjerre M. Soluble receptor for advanced glycation end product: a biomarker for acute coronary syndrome. Biomed Res Int. 2015;2015:815942.

    PubMed  PubMed Central  Google Scholar 

  40. Grauen Larsen H, Marinkovic G, Nilsson PM, Nilsson J, Engstrom G, Melander O, et al. High plasma sRAGE (soluble receptor for advanced glycation end products) is associated with slower carotid intima-media thickness progression and lower risk for first-time coronary events and mortality. Arterioscler Thromb Vasc Biol. 2019;39:925–33.

    CAS  PubMed  Google Scholar 

  41. Prasad K. Is there any evidence that AGE/sRAGE is a universal biomarker/risk marker for diseases? Mol Cell Biochem. 2019;451:139–44.

    CAS  PubMed  Google Scholar 

  42. Tam HL, Shiu SW, Wong Y, Chow WS, Betteridge DJ, Tan KC. Effects of atorvastatin on serum soluble receptors for advanced glycation end-products in type 2 diabetes. Atherosclerosis. 2010;209:173–7.

    CAS  PubMed  Google Scholar 

  43. Forbes JM, Thorpe SR, Thallas-Bonke V, Pete J, Thomas MC, Deemer ER, et al. Modulation of soluble receptor for advanced glycation end products by angiotensin-converting enzyme-1 inhibition in diabetic nephropathy. J Am Soc Nephrol. 2005;16:2363–72.

    CAS  PubMed  Google Scholar 

  44. Tan KCB, Chow WS, Tso AWK, Xu A, Tse HF, Hoo RLC, et al. Thiazolidinedione increases serum soluble receptor for advanced glycation end-products in type 2 diabetes. Diabetologia. 2007;50:1819–25.

    CAS  PubMed  Google Scholar 

  45. Tang SC, Wang YC, Li YI, Lin HC, Manzanero S, Hsieh YH, et al. Functional role of soluble receptor for advanced glycation end products in stroke. Arterioscler Thromb Vasc Biol. 2013;33:585–94.

    CAS  PubMed  Google Scholar 

  46. Sakaguchi T, Yan SF, Yan SD, Belov D, Rong LL, Sousa M, et al. Central role of RAGE-dependent neointimal expansion in arterial restenosis. J Clin Investig. 2003;111:959–72.

    CAS  PubMed  Google Scholar 

  47. Wautier JL, Zoukourian C, Chappey O, Wautier MP, Guillausseau PJ, Cao R, et al. Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats. J Clin Investig. 1996;97:238–43.

    CAS  PubMed  Google Scholar 

  48. Kass DA, Shapiro EP, Kawaguchi M, Capriotti AR, Scuteri A, deGroof RC, et al. Improved arterial compliance by a novel advanced glycation end-product crosslink breaker. Circulation. 2001;104:1464–70.

    CAS  PubMed  Google Scholar 

  49. Oudegeest-Sander MH, Olde Rikkert MG, Smits P, Thijssen DH, van Dijk AP, Levine BD, et al. The effect of an advanced glycation end-product crosslink breaker and exercise training on vascular function in older individuals: a randomized factorial design trial. Exp Gerontol. 2013;48:1509–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Bakris GL, Bank AJ, Kass DA, Neutel JM, Preston RA, Oparil S. Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process. Am J Hypertens. 2004;17:23s–30s.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The study was supported by the Health Development Agency of the Czech Ministry of Health (project 15-27109) and by the Charles University Research Fund (PROGRES, project Q39). We would like to acknowledge the hard work of all investigators and other coworkers (study nurses, laboratory technicians, and medical students) who participated in the post-MONICA project, and last but not least all study subjects, who voluntarily participate in the very time-consuming clinical examination program.

Author information

Authors and Affiliations

  1. 2nd Department of Internal Medicine, Medical Faculty of Charles University and University Hospital, Pilsen, Czech Republic

    Július Gelžinský, Otto Mayer Jr., Jitka Seidlerová, Markéta Mateřánková, Štěpán Mareš, Veronika Kordíková & Jan Filipovský

  2. Biomedical Center, Medical Faculty of Charles University, Pilsen, Czech Republic

    Július Gelžinský, Otto Mayer Jr., Jitka Seidlerová, Markéta Mateřánková, Štěpán Mareš, Veronika Kordíková & Jan Filipovský

  3. Department of Clinical Biochemistry and Hematology, University Hospital, Pilsen, Czech Republic

    Ladislav Trefil

  4. Centre for Cardiovascular Prevention of the First Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czech Republic

    Renata Cífková

Authors
  1. Július Gelžinský
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Otto Mayer Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jitka Seidlerová
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Markéta Mateřánková
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Štěpán Mareš
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Veronika Kordíková
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ladislav Trefil
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Renata Cífková
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jan Filipovský
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Otto Mayer Jr..

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gelžinský, J., Mayer Jr., O., Seidlerová, J. et al. Soluble receptor for advanced glycation end-products independently influences individual age-dependent increase of arterial stiffness. Hypertens Res 43, 111–120 (2020). https://doi.org/10.1038/s41440-019-0347-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41440-019-0347-y

Keywords

This article is cited by

Search

Advanced search

Quick links