Glycoconjugate Journal

, Volume 35, Issue 5, pp 443–450 | Cite as

Role of AGEs in the progression and regression of atherosclerotic plaques

  • Zhong-qun WangEmail author
  • Le-le Jing
  • Jin-chuan Yan
  • Zhen Sun
  • Zheng-yang Bao
  • Chen Shao
  • Qi-wen Pang
  • Yue Geng
  • Li-li Zhang
  • Li-hua LiEmail author
Review Article


The formation of advanced glycation end-products(AGEs) is an important cause of metabolic memory in diabetic patients and a key factor in the formation of atherosclerosis(AS) plaques in patients with diabetes mellitus. Related studies showed that AGEs could disrupt hemodynamic steady-state and destroy vascular wall integrity through the endothelial barrier damage, foam cell(FC) formation, apoptosis, calcium deposition and other aspects. At the same time, AGEs could initiate oxidative stress and inflammatory response cascade via receptor-depended and non-receptor-dependent pathways, promoting plaques to develop from a steady state to a vulnerable state and eventually tend to rupture and thrombosis. Numerous studies have confirmed that these pathological processes mentioned above could lead to acute coronary heart disease(CHD) and other acute cardiovascular and cerebrovascular events. However, the specific role of AGEs in the progression and regression of AS plaques has not yet been fully elucidated. In this paper, the formation, source, metabolism, physical and chemical properties of AGEs and their role in the migration of FCs and plaque calcification are briefly described, we hope to provide new ideas for the researchers that struggling in this field.


Advanced glycation end-products Foam cell migration Plaque calcification Atherosclerosis 



advanced glycation end-products




foam cell


coronary heart disease


vascular calcification


vascular smooth muscle cell


apoptotic body




Availability of data and materials

Not applicable.

Authors’ contributions

All authors contributed to conception and design and wrote the review; All authors read and approved the final manuscript.


This work was supported by the National Natural Science Foundation of China (Grant Nos. 81770450, 81370408, 81670105); Jiangsu Provincial Health and Family Planning Commission project(QNRC2016836); the Open Program of Key Laboratory of Nuclear Medicine, Ministry of Health and Jiangsu Key Laboratory of Molecular Nuclear Medicine(KF201504); Innovation plan for postgraduate research in Jiangsu Province(KYCX17_1801).

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no competing interests.

Ethical approval

Not applicable.


  1. 1.
    Singh, V.P., Bali, A., Singh, N., Jaggi, A.S.: Advanced glycation end products and diabetic complications[J]. Korean J Physiol Pharmacol. 18(1), 1–14 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Wang, Z., Jiang, Y., Liu, N., Ren, L., Zhu, Y., An, Y., Chen, D.: Advanced glycation end-product Nε-carboxymethyl-lysine accelerates progression of atherosclerotic calcification in diabetes. Atherosclerosis. 221(2), 387–396 (2012)CrossRefPubMedGoogle Scholar
  3. 3.
    Criqui, M.H., Denenberg, J.O., Ix, J.H., et al.: Calcium density of coronary artery plaque and risk of incident cardiovascular events[J]. JAMA. 3(3), 271–278 (2014)CrossRefGoogle Scholar
  4. 4.
    Pugliese, G., Iacobini, C., Blasetti, F.C., et al.: The dark and bright side of atherosclerotic calcification [J]. Atherosclerosis. 238(2), 220–230 (2015)CrossRefPubMedGoogle Scholar
  5. 5.
    Otsuka, F., Sakakura, K., Yahagi, K., Joner, M., Virmani, R.: Has our understanding of calcification in human coronary atherosclerosis progressed? Arterioscler. Thromb. Vasc. Biol. 34(4), 724–736 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Giacheli, C.M.: Inducers and inhibitors of biomineralization: lessons from pathological calcification [J]. Orthod. Craniofacial Res. 8(4), P229–231–P229–229 (2005)CrossRefGoogle Scholar
  7. 7.
    Bobryshev, Y.V.: Transdifferentiation of smooth muscle cells into chondrocytes in atherosclerotic arteries in situ: implications for diffuse intimal calcification. J. Pathol. 205, 641–650 (2005)CrossRefPubMedGoogle Scholar
  8. 8.
    Ruiz JL, Hutcheson JD, Aikawa E. Cardiovascular calcification: current controversies and novel concepts. 2015 24(4), 207–212Google Scholar
  9. 9.
    Goel, R., Garg, P., Achenbach, S., Gupta, A., Song, J.J., Wong, N.D., Shaw, L.J., Narula, J.: Coronary artery calcification and coronary atherosclerotic disease. Cardiol. Clin. 30(1), 19–47 (2012 Feb)CrossRefPubMedGoogle Scholar
  10. 10.
    Kalanuria, A.A., Nyquist, P., Ling, G.: The prevention and regression of atherosclerotic plaques:emerging treatments. Vasc. Health Risk Manag. 8, 549–561 (2012)PubMedPubMedCentralGoogle Scholar
  11. 11.
    Curtiss, L.K.: Reversing atherosclerosis? [J]. N. Engl. J. Med. 360, 1144–1146 (2009)CrossRefPubMedGoogle Scholar
  12. 12.
    Feig, J.E., Vengrenyuk, Y., Reiser, V., et al.: Regression of atherosclerosis is characterized by broad changes in the plaque macrophage transcriptome. PLoS One. 7, e39790 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Williams, K.J., Feig, J.E., Fisher, E.A.: Rapid regression of atherosclerosis: insights from the clinical and experimental literature. Nat. Rev. Cardiol. 5, 91–102 (2008)CrossRefGoogle Scholar
  14. 14.
    Williams, K.J., Feig, J.E., Fisher, E.A.: Cellular and molecular mechanisms for rapid regression of atherosclerosis: from bench top to potentially achievable clinical goal. Curr. Opin. Lipidol. 18(4), 443–450 (2007 Aug)CrossRefPubMedGoogle Scholar
  15. 15.
    Vistoli, G., De Maddis, D., Cipak, A., et al.: Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation. Free Radic. Res. 47(Suppl 1), 3–27 (2013 Aug)CrossRefPubMedGoogle Scholar
  16. 16.
    Shen, C., Li, Q., Zhang, Y.C., Ma, G., Feng, Y., Zhu, Q., Dai, Q., Chen, Z., Yao, Y., Chen, L., Jiang, Y., Liu, N.: Advanced glycation end products increase EPC apoptosis and decrease nitric oxide release via MAPK pathways[J]. Biomed Pharmacother. 64(1), 35–43 (2010 Jan)CrossRefPubMedGoogle Scholar
  17. 17.
    Ikeda, T., Maruyama, K., et al.: Higher serum pentosidine, an advanced glycation end product, in branch atheromatous disease among small vessels occlusion. J. Neurosurg. Sci. (2016 Feb 19)Google Scholar
  18. 18.
    Xu, H., Wang, Z., Wang, Y., et al.: Biodistribution and elimination study of fluorine-18 labeled Nε-carboxymethyl-lysine following intragastric and intravenous administration [J]. PLoS One. 8(3), 1–10 (2013)CrossRefGoogle Scholar
  19. 19.
    Ajith, T.A., Vinodkumar, P.: Advanced glycation end products: association with the pathogenesis of diseases and the current therapeutic advances. Curr. Clin. Pharmacol. 11(2), 118–127 (2016)CrossRefPubMedGoogle Scholar
  20. 20.
    Semba, R.D., Arab, L., Sun, K., Nicklett, E.J., Ferrucci, L.: Fat mass is inversely associated with serum carboxymethyl-lysine,an advanced glycation end product,in adults. J. Nutr. 141, 1726–1730 (2011)CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Prasad, A., Bekker, P., Tsimikas, S.: Advanced glycation end products and diabetic cardiovascular disease [J]. Cardiol. Rev. 4, 177–183 (2012 Jul-Aug)CrossRefGoogle Scholar
  22. 22.
    Wang, Y., Zhang, Z.Y., Chen, X.Q., Wang, X., Cao, H., Liu, S.W.: Advanced glycation end products promote human aortic smooth muscle cell calcification in vitro via activating NF-κB and down-regulating IGF1R expression. Acta Pharmacol. Sin. 34(4), 480–486 (2013 Apr)CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Ren, X., Shao, H., Wei, Q., Sun, Z., Liu, N.: Advanced glycation end-products enhance calcification in vascular smooth muscle cells. J Int Med Res. 37(3), 847–854 (2009 May-Jun)CrossRefPubMedGoogle Scholar
  24. 24.
    Brodeur, M.R., Bouvet, C.R., Bouchard, S., Moreau, S., Leblond, J., deBlois, D., Moreau, P.: Reduction of advanced-glycation end products levels and inhibition of RAGE signaling decreases rat vascular calcification induced by diabetes. PLoS One. 9(1), e85922 (2014 Jan 21)CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Menini, S., Iacobini, C., Ricci, C., Blasetti Fantauzzi, C., Salvi, L., Pesce, C.M., Relucenti, M., Familiari, G., Taurino, M., Pugliese, G.: The galectin-3/RAGE dyad modulates vascular osteogenesis in atherosclerosis. Cardiovasc. Res. 100(3), 472–480 (2013)CrossRefPubMedGoogle Scholar
  26. 26.
    Mozos, I., Malainer, C., Horbańczuk, J., Gug, C., Stoian, D., Luca, C.T., Atanasov, A.G.: Inflammatory markers for arterial stiffness in cardiovascular diseases. Front. Immunol. 8, 1058 (2017)CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Yamada, S., Taniguchi, M., Tokumoto, M., Toyonaga, J., Fujisaki, K., Suehiro, T., Noguchi, H., Iida, M., Tsuruya, K., Kitazono, T.: The antioxidant tempol ameliorates arterial medial calcification in uremic rats: important role of oxidative stress in the pathogenesis of vascular calcification in chronic kidney disease. J. Bone Miner. Res. 27(2), 474–485 (2012 Feb)CrossRefPubMedGoogle Scholar
  28. 28.
    Kay, A.M., Simpson, C.L., Stewart Jr., J.A.: The role of AGE/RAGE signaling in diabetes-mediated vascular calcification. J Diabetes Res. 2016, 6809703 (2016)CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Sutra, T., Morena, M., Bargnoux, A.S., Caporiccio, B., Canaud, B., Cristol, J.P.: Superoxide production: a procalcifying cell signalling event in osteoblastic differentiation of VSMCs exposed to calcification media. Free Radic. Res. 42, 789–797 (2008)CrossRefPubMedGoogle Scholar
  30. 30.
    Kennedy, J.A., Hua, X., Mishra, K., Murphy, G.A., Rosenkranz, A.C., Horowitz, J.D.: Inhibition of calcifying nodule formation in cultured porcine aortic valve cells by nitric oxide donors. Eur. J. Pharmacol. 602, 28–35 (2009)CrossRefPubMedGoogle Scholar
  31. 31.
    Liberman, M., Bassi, E., Martinatti, M.K., Lario, F.C., Wosniak, J., Pomerantzeff, P.M.A., Laurindo, F.R.M.: Oxidant generation predominates around calcifying foci and enhances progression of aortic valve calcification. Arterioscler. Thromb. Vasc. Biol. 28, 463–470 (2008)CrossRefPubMedGoogle Scholar
  32. 32.
    You, H., Yang, H., Zhu, Q., Li, M., Xue, J., Gu, Y., Lin, S., Ding, F.: Advanced oxidation protein products induce vascular calcification by promoting osteoblastic trans-differentiation of VSMCs via oxidative stress and ERK pathway. Ren. Fail. 31, 313–319 (2009)CrossRefPubMedGoogle Scholar
  33. 33.
    Byon, C.H., Javed, A., Dai, Q., Kappes, J.C., Clemens, T.L., Darley-Usmar, V.M., McDonald, J.M., Chen, Y.: Oxidative stress induces vascular calcification through modulation of the osteogenic transcription factor Runx2 by AKT signaling. J. Biol. Chem. 283, 15319–15327 (2008)CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Benito, M., Chen-Charpentier, A., et al.: A mathematical model of bone remodeling with delays. J. Comput. Appl. Math. 291, 76–84 (2016)CrossRefGoogle Scholar
  35. 35.
    Molinuevo, M.S., Fernández, J.M., Cortizo, A.M., McCarthy, A.D., Schurman, L., Sedlinsky, C.: Advanced glycation end products and strontium ranelate promote osteogenic differentiation of VSMCs in vitro: preventive role of vitamin D. Mol. Cell. Endocrinol. 450, 94–104 (2017)CrossRefPubMedGoogle Scholar
  36. 36.
    Miyata, T., Notoya, K., et al.: Advanced glycation end products enhance osteoclast-induced bone resorption in cultured mouse unfractionated bone cells and in rats implanted subcutaneously with devitalized bone particles. J. Am. Soc. Nephrol. 8(2), 260–270 (1997 Feb)PubMedGoogle Scholar
  37. 37.
    Li, G., Xu, J., Li, Z.: Receptor for advanced glycation end products inhibits proliferation in osteoblast through suppression of Wnt, PI3K and ERK signaling[J]. Biochem. Biophys. Res. Commun. 423(4), 684–689 (2012)CrossRefPubMedGoogle Scholar
  38. 38.
    Takino, J., Nagamine, K., Hori, T., Sakasai-Sakai, A., Takeuchi, M.: Contribution of the toxic advanced glycation end-products-receptor axis in nonalcoholic steatohepatitis-related hepatocellular carcinoma. World J. Hepatol. 7(23), 2459–2469 (2015 Oct)CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Marcus, B., Tom, R., et al.: Association between carotid diameter and the advanced glycation end product Nε-Carboxymethyllysine (CML). Cardiovasc. Diabetol. 8, 45 (2009)CrossRefGoogle Scholar
  40. 40.
    Demiryurek, B.E., Gundogdu, A.A., Fetuin-A, S.: Levels in patients with bilateral basal ganglia calcification. Neurosci. Lett. 666, 148–152 (2017)CrossRefPubMedGoogle Scholar
  41. 41.
    Janda, K., Krzanowski, M., Gajda, M., et al.: Vascular effects of advanced glycation end-products: content of immunohistochemically detected AGEs in radial artery samples as a predictor for arterial calcification and cardiovascular risk in asymptomatic patients with chronic kidney disease [J]. Dis. Markers. 153978, 2015 (2015)Google Scholar
  42. 42.
    Duan, X.H., Chang, J.R., Zhang, J., Zhang, B.H., Li, Y.L., Teng, X., Zhu, Y., du, J., Tang, C.S., Qi, Y.F.: Activating transcription factor 4 is involved in endoplasmic reticulum stress-mediated apoptosis contributing to vascular calcification. Apoptosis. 18(9), 1132–1144 (2013 Sep)CrossRefGoogle Scholar
  43. 43.
    Wang, Z., Yan, J., Li, L., Liu, N., Liang, Y., Yuan, W., Chen, X.: Effects of Nε-carboxymethyl-lysine on ERS-mediated apoptosis in diabetic atherosclerosis. Int. J. Cardiol. 172(3), e478–e483 (2014)CrossRefPubMedGoogle Scholar
  44. 44.
    Wang, Z., Li, L., Du, R., et al.: CML/RAGE signal induces calcification cascade in diabetes. Diabetol. Metab. Syndr. 83(1–12), 8 (2016)Google Scholar
  45. 45.
    Ramsey, S.A., Vengrenyuk, Y., Menon, P., Podolsky, I., Feig, J.E., Aderem, A., Fisher, E.A., Gold, E.S.: Epigenome-guided analysis of the transcriptome of plaque macrophages during atherosclerosis regression reveals activation of the Wnt signaling pathway. PLoS Genet. 10(12), e1004828 (2014 Dec 4)CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Cipres, A., O'Malley, D.P., Li, K., et al.: Sceptrin, a marine natural compound, inhibits cell motility in a variety of cancer cell lines[J]. ACS Chem. Biol. 5(2), 195–202 (2010 Feb)CrossRefPubMedGoogle Scholar
  47. 47.
    Xu, S., Li, L., Yan, J., Ye, F., Shao, C., Sun, Z., Bao, Z., Dai, Z., Zhu, J., Jing, L., Wang, Z.: CML/CD36 accelerates atherosclerotic progression via inhibiting foam cell migration. Biomed Pharmacother. 97, 1020–1031 (2018 Jan)CrossRefPubMedGoogle Scholar
  48. 48.
    Park YM, Febbraio M, Silverstein RL. CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intima [J]. J. Clin. Invest., 2009, 119(1):136–145Google Scholar
  49. 49.
    Sun, H., Yuan, Y., Sun, Z.: Update on mechanisms of renal tubule injury caused by advanced glycation end products. Biomed. Res. Int. 2016, 5475120 (2016)PubMedPubMedCentralGoogle Scholar
  50. 50.
    Xanthis, A., Hatzitolios, A., Fidani, S., Befani, C., Giannakoulas, G., Koliakos, G.: Receptor of advanced glycation end products(RAGE) positively regulates CD36 expression and reactive oxygen species production in human monocytes in diabetes[J]. Angiology. 60(6), 772–779 (2009)CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Zhong-qun Wang
    • 1
    Email author
  • Le-le Jing
    • 1
  • Jin-chuan Yan
    • 1
  • Zhen Sun
    • 1
  • Zheng-yang Bao
    • 1
  • Chen Shao
    • 1
  • Qi-wen Pang
    • 1
  • Yue Geng
    • 1
  • Li-li Zhang
    • 1
  • Li-hua Li
    • 2
    Email author
  1. 1.Department of CardiologyAffiliated Hospital of Jiangsu UniversityZhenjiangChina
  2. 2.Department of PathologyAffiliated Hospital of Jiangsu UniversityZhenjiangChina

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