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Role of AGEs in the progression and regression of atherosclerotic plaques

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Abstract

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.

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Abbreviations

AGEs:

advanced glycation end-products

AS:

atherosclerosis

FC:

foam cell

CHD:

coronary heart disease

VC:

vascular calcification

VSMC:

vascular smooth muscle cell

AB:

apoptotic body

CML:

Nε-Carboxymethyllysine

References

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Giacheli, C.M.: Inducers and inhibitors of biomineralization: lessons from pathological calcification [J]. Orthod. Craniofacial Res. 8(4), P229–231–P229–229 (2005)

    Article  Google Scholar 

  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)

    Article  PubMed  Google Scholar 

  8. Ruiz JL, Hutcheson JD, Aikawa E. Cardiovascular calcification: current controversies and novel concepts. 2015 24(4), 207–212

  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)

    Article  PubMed  Google Scholar 

  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)

    PubMed  PubMed Central  Google Scholar 

  11. Curtiss, L.K.: Reversing atherosclerosis? [J]. N. Engl. J. Med. 360, 1144–1146 (2009)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

  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)

    Article  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Prasad, A., Bekker, P., Tsimikas, S.: Advanced glycation end products and diabetic cardiovascular disease [J]. Cardiol. Rev. 4, 177–183 (2012 Jul-Aug)

    Article  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Benito, M., Chen-Charpentier, A., et al.: A mathematical model of bone remodeling with delays. J. Comput. Appl. Math. 291, 76–84 (2016)

    Article  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  40. Demiryurek, B.E., Gundogdu, A.A., Fetuin-A, S.: Levels in patients with bilateral basal ganglia calcification. Neurosci. Lett. 666, 148–152 (2017)

    Article  CAS  PubMed  Google Scholar 

  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. 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)

    Article  CAS  Google Scholar 

  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)

    Article  PubMed  Google Scholar 

  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. 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)

    Article  PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

  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):136–145

  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)

    PubMed  PubMed Central  Google Scholar 

  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)

    Article  CAS  PubMed  Google Scholar 

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Funding

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).

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  1. Zhong-qun Wang and Le-le Jing contributed equally to this work and should be considered co-first authors.

Authors and Affiliations

  1. Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China

    Zhong-qun Wang, Le-le Jing, Jin-chuan Yan, Zhen Sun, Zheng-yang Bao, Chen Shao, Qi-wen Pang, Yue Geng & Li-li Zhang

  2. Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China

    Li-hua Li

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  1. Zhong-qun Wang
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  2. Le-le Jing
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All authors contributed to conception and design and wrote the review; All authors read and approved the final manuscript.

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Correspondence to Zhong-qun Wang or Li-hua Li.

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Wang, Zq., Jing, Ll., Yan, Jc. et al. Role of AGEs in the progression and regression of atherosclerotic plaques. Glycoconj J 35, 443–450 (2018). https://doi.org/10.1007/s10719-018-9831-x

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