Skip to main content

Advertisement

SpringerLink
Log in

The role of advanced glycation end products in the development of atherosclerosis

  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Cardiovascular disease (CVD) is the leading cause of mortality worldwide. Atherosclerosis constitutes the main pattern of cardiovascular disease and leads to thickening of the intima with plaque formation and eventual occlusion of the arterial lumen. A large amount of evidence links advanced glycation end products (AGEs) with the development or progression of atherosclerosis, regardless of the diabetic status. AGEs are a heterogenous group of compounds formed by the nonenzymatic reaction of reducing sugars with proteins, lipids, and nucleic acids. Although AGEs are formed endogenously in the body, diet has recently been recognized as an important exogenous source. An increased understanding of the mechanisms of formation and interaction of AGEs has allowed the development of several potential anti-AGE approaches.

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

Similar content being viewed by others

References and Recommended Reading

  1. Murray CJ, Lopez AD: Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet 1997, 349:1498–1504.

    Article  PubMed  CAS  Google Scholar 

  2. Yusuf HR, Giles WH, Croft JB, et al.: Impact of multiple risk factor profiles on determining cardiovascular disease risk. Prev Med 1998, 27:1–9.

    Article  PubMed  CAS  Google Scholar 

  3. Baynes JW, Thorpe SR: Glycoxidation and lipoxidation in atherogenesis. Free Radic Biol Med 2000, 28:1708–1716.

    Article  PubMed  CAS  Google Scholar 

  4. Nerlich AG, Schleicher ED: N ∈-(carboxymethyl)lysine in atherosclerotic vascular lesions as a marker for local oxidative stress. Atherosclerosis 1999, 144:41–47.

    Article  PubMed  CAS  Google Scholar 

  5. Sims TJ, Rasmussen LM, Oxlund H, Bailey AJ: The role of glycation cross-links in diabetic vascular stiffening. Diabetologia 1996, 39:946–951.

    PubMed  CAS  Google Scholar 

  6. Stitt AW, He C, Friedman S, et al.: Elevated AGE-modified apoB in sera of euglycemic, normolipidemic patients with atherosclerosis: relation to tissue AGE. Mol Med 1997, 3:617–627.

    PubMed  CAS  Google Scholar 

  7. Vlassara H, Palace MR: Diabetes and advanced glycation end products. J Intern Med 2002, 251:87–101.

    Article  PubMed  CAS  Google Scholar 

  8. Fu MX, Requena JR, Jenkins AJ, et al.: The advanced glycation end product, N_-(carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation reactions. J Biol Chem 1996, 271:9982–9986.

    Article  PubMed  CAS  Google Scholar 

  9. Nicholl ID, Bucala R: Advanced glycation end products and cigarette smoking. Cell Mol Biol (Noisy-le-grand) 1998, 44:1025–1033.

    CAS  Google Scholar 

  10. Lee T, Kimiagar M, Pintauro SJ, Chichester CO: Physiological and safety aspects of Maillard browning of foods. Prog Food Nutr Sci 1981, 5:243–256.

    PubMed  CAS  Google Scholar 

  11. Koschinsky T, He CJ, Mitsuhashi T, et al.: Orally absorbed reactive advanced glycation end products (glycotoxins): an environmental risk factor in diabetic nephropathy. Proc Natl Acad Sci U S A 1997, 94:6474–6479.

    Article  PubMed  CAS  Google Scholar 

  12. He C, Sabol J, Mitsuhashi T, Vlassara H: Dietary glycotoxins: inhibition of reactive products by aminoguanidine facilitates renal clearance and reduces tissue sequestration. Diabetes 1999, 48:1308–1315.

    Article  PubMed  CAS  Google Scholar 

  13. Cai W, Cao Q, Zhu L, et al.: Oxidative stress-inducing carbonyl compounds from common foods: novel mediators of cellular dysfunction. Mol Med 2002, 8:337–346.

    PubMed  CAS  Google Scholar 

  14. Zheng F, He C, Cai W, et al.: Prevention of diabetic nephropathy in mice by a diet low in glycoxidation products. Diabetes Metab Res Rev 2002, 18:224–237.

    Article  PubMed  Google Scholar 

  15. Peppa M, Brem H, Ehrlich P, et al.: Adverse effects of dietary glycotoxins on wound healing in genetically diabetic mice. Diabetes 2003, 52:2805–2813.

    Article  PubMed  CAS  Google Scholar 

  16. Lin RY, Reis ED, Dore AT, et al.: Lowering of dietary advanced glycation end products (AGE) reduces neointimal formation after arterial injury in genetically hypercholesterolemic mice. Atherosclerosis 2002, 163:303–311.

    Article  PubMed  CAS  Google Scholar 

  17. Lin RY, Choudhury RP, Cai W, et al.: Dietary glycotoxins promote diabetic atherosclerosis in apolipoprotein E-deficient mice. Atherosclerosis 2003, 168:213–220.

    Article  PubMed  CAS  Google Scholar 

  18. Sebekova K, Faist V, Hofmann T, et al.: Effects of a diet rich in advanced glycation end products in the rat remnant kidney model. Am J Kidney Dis 2003, 41(3 suppl 1):S48-S51.

    PubMed  Google Scholar 

  19. Peppa M, HE C, Hattori M, et al.: Fetal or neonatal lowglycotoxin environment prevents autoimmune diabetes in NOD mice. Diabetes 2003, 52:1441–1448.

    Article  PubMed  CAS  Google Scholar 

  20. Hofmann SM, Dong HJ, Li Z, et al.: Improved insulin sensitivity is associated with restricted intake of dietary glycoxidation products in the db/db mouse. Diabetes 2002, 51:2082–2089.

    Article  PubMed  CAS  Google Scholar 

  21. Vlassara H, Cai W, Crandall J, et al.: Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy. Proc Natl Acad Sci U S A 2002, 99:15596–15601. Shows for the first time that a diet low in AGE content diminishes the serum AGE levels, as well as levels of circulating markers of inflammation and endothelial dysfunction, in humans. This raises the therapeutic possibility of using dietary intervention to diminish the body AGE burden.

    Article  PubMed  CAS  Google Scholar 

  22. Uribarri J, Peppa M, Cai W, et al.: Dietary glycotoxins correlate with circulating advanced glycation end product levels in renal failure patients. Am J Kid Dis 2003, 42:532–538. Demonstrates for the first time a significant correlation between dietary content of AGEs and serum levels of AGEs, providing support to the postulation that dietary AGEs are important contributors to the body AGE burden.

    Article  PubMed  CAS  Google Scholar 

  23. Uribarri J, Peppa M, Cai W, et al.: Restriction of dietary glycotoxins markedly reduces AGE toxins in renal failure patients. J Am Soc Nephrol 2003, 14:728–731.

    Article  PubMed  CAS  Google Scholar 

  24. Gugliucci A, Bendayan M: Renal fate or circulating advanced glycated end products (AGE): evidence for reabsorption and catabolism of AGE-peptides by renal proximal tubular cells. Diabetologia 1996, 39:140–160.

    Article  Google Scholar 

  25. Makita Z, Radoff S, Rayfield EJ, et al.: Advanced glycosylation end products in patients with diabetic nephropathy. N Engl J Med 1991, 325:836–842.

    Article  PubMed  CAS  Google Scholar 

  26. Shinohara M, Thornalley PJ, Giardino I, et al.: Overexpression of glyoxalase-I in bovine endothelial cells inhibits intracellular advanced glycation end product formation and prevents hyperglycemia-induced increases in macromolecular endocytosis. J Clin Invest 1998, 101:1142–1147.

    PubMed  CAS  Google Scholar 

  27. Vlassara H: The AGE-receptor in the pathogenesis of diabetic complications. Diabetes Metab Res Rev 2001, 17:436–443.

    Article  PubMed  CAS  Google Scholar 

  28. Sakurai S, Yonekura H, Yamamoto Y, et al.: The AGE-RAGE system and diabetic nephropathy. J Am Soc Nephrol 2003, 14:S259-S263.

    Article  PubMed  CAS  Google Scholar 

  29. Zheng F, Cai W, Mitsuhashi T, Vlassara H: Lysozyme enhances renal excretion of advanced glycation end products in vivo and suppresses adverse age-mediated cellular effects in vitro: a potential AGE sequestration therapy for diabetic nephropathy? Mol Med 2001, 7:737–747.

    PubMed  CAS  Google Scholar 

  30. Bucala R, Tracey KJ, Cerami A: Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest 1991, 87:432–438.

    PubMed  CAS  Google Scholar 

  31. Rumble JR, Cooper ME, Soulis T, et al.: Vascular hypertrophy in experimental diabetes: role of advanced glycation end products. J Clin Invest 1997, 99:1016–1027.

    Article  PubMed  CAS  Google Scholar 

  32. Bucala R, Mitchell R, Arnold K, et al.: Identification of the major site of apolipoprotein B modification by advanced glycosylation end products blocking uptake by the low density lipoprotein receptor. J Biol Chem 1995, 270:10828–10832.

    Article  PubMed  CAS  Google Scholar 

  33. Zhang J, Ren S, Sun D, Shen GX: Influence of glycation on LDL-induced generation of fibrinolytic regulators in vascular endothelial cells. Arterioscler Thromb Vasc Biol 1998, 18:1140–1148.

    PubMed  CAS  Google Scholar 

  34. Hedrick CC, Thorpe SR, Fu MX, et al.: Glycation impairs high-density lipoprotein function. Diabetologia 2000, 43:312–320.

    Article  PubMed  CAS  Google Scholar 

  35. Zhang J, Ren S, Shen GX: Glycation amplifies lipoprotein(a)-induced alterations in the generation of fibrinolytic regulators from human vascular endothelial cells. Atherosclerosis 2000, 150:299–308.

    Article  PubMed  CAS  Google Scholar 

  36. Lassegue B, Clempus RE: Vascular NAD(P)H oxidases: specific features, expression, and regulation. Am J Physiol Regul Integr Comp Physiol 2003, 285:R277-R297.

    PubMed  CAS  Google Scholar 

  37. Panagiotopoulos S, O'Brien RC, Bucala R, et al.: Aminoguanidine has an anti-atherogenic effect in the cholesterol-fed rabbit. Atherosclerosis 1998, 136:125–131.

    Article  PubMed  CAS  Google Scholar 

  38. Palinski W, Koschinsky T, Butler SW, et al.: Immunological evidence for the presence of advanced glycation end products in atherosclerotic lesions of euglycemic rabbits. Arterioscler Thromb Vasc Biol 1995, 15:571–582.

    PubMed  CAS  Google Scholar 

  39. Vlassara H, Fuh H, Donnelly T, Cybulsky M: Advanced glycation end products promote adhesion molecule (VCAM-1, ICAM-1) expression and atheroma formation in normal rabbits. Mol Med 1995, 1:447–456.

    PubMed  CAS  Google Scholar 

  40. Vlassara H, Fuh H, Makita Z, et al.: Exogenous advanced glycosylation end products induce complex vascular dysfunction in normal animals: a model for diabetic and aging complications. Proc Natl Acad Sci U S A 1992, 89:12043–12047.

    Article  PubMed  CAS  Google Scholar 

  41. Wautier JL, Zoukourian C, Chappey O, et al.: Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats. J Clin Invest 1996, 97:238–243.

    PubMed  CAS  Google Scholar 

  42. Crauwels HM, Herman AG, Bult H: Local application of advanced glycation end products and intimal hyperplasia in the rabbit collared carotid artery. Cardiovasc Res 2000, 40:173–182.

    Article  Google Scholar 

  43. Brownlee M, Vlassara H, Kooney A, et al.: Aminoguanidine prevents diabetes-induced arterial wall protein crosslinking. Science 1986, 232:1629–1632.

    Article  PubMed  CAS  Google Scholar 

  44. Miyata T, Ishikawa S, Asahi K, et al.: 2-Isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide (OPB-9195) treatment inhibits the development of intimal thickening after balloon injury of rat carotid artery: role of glycoxidation and lipoxidation reactions in vascular tissue damage. FEBS Lett 1999, 445:202–206.

    Article  PubMed  CAS  Google Scholar 

  45. Park I, Raman KG, Lee KJ, et al.: Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation end products. Nat Med 1998, 4:1025–1031.

    Article  PubMed  CAS  Google Scholar 

  46. Wolffenbuttel BH, Boulanger CM, Crijns FR, et al.: Breakers of advanced glycation end products restore large artery properties in experimental diabetes. Proc Natl Acad Sci U S A 1998, 95:4630–4634.

    Article  PubMed  CAS  Google Scholar 

  47. Vaitkevicius PV, Lane M, Spurgeon H, et al.: A cross-link breaker has sustained effects on arterial and ventricular properties in older rhesus monkeys. Proc Natl Acad Sci U S A 2001, 98:1171–1175.

    Article  PubMed  CAS  Google Scholar 

  48. Vasan S, Foiles PG, Founds HW: Therapeutic potential of AGE inhibitors and breakers of AGE protein cross-links. Expert Opin Investig Drugs 2001, 10:1977–1987.

    Article  PubMed  CAS  Google Scholar 

  49. Nakamura Y, Horii Y, Nishino T, et al.: Immunohistochemical localization of advanced glycosylation end products in coronary atheroma and cardiac tissue in diabetes mellitus. Am J Pathol 1993, 143:1649–1656.

    PubMed  CAS  Google Scholar 

  50. 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 Invest 1997, 99:457–468.

    PubMed  CAS  Google Scholar 

  51. Yamada K, Miyahara Y, Hamaguchi K, et al.: Immunohistochemical study of human advanced glycation end-products in chronic renal failure. Clin Nephrol 1994, 42:354–361.

    PubMed  CAS  Google Scholar 

  52. Tan KC, Chow WS, Ai VH, et al.: Advanced glycation end products and endothelial dysfunction in type 2 diabetes. Diabetes Care 2002, 25:1055–1059.

    Article  PubMed  CAS  Google Scholar 

  53. Kass DA, Sapiro EP, Kawaguchi M, et al.: Improved arterial compliance by a novel advanced glycation end-product crosslink breaker. Circulation 2001, 104:1464–1470. The first time that a drug is shown to increase arterial distensibility in humans; this work opens the possibility of the use of AGE breakers to directly modify vascular disease.

    PubMed  CAS  Google Scholar 

  54. Stirban A, Sander D, Buenting C, et al.: Food advanced glycation end products (AGE) acutely impair endothelial function in patients wit diabetes mellitus [abstract]. Diabetes 2003, 52(suppl 1):A19.

    Google Scholar 

  55. Nangaku M, Miyata T, Sada T, et al.: Anti-hypertensive agents inhibit in vivo the formation of advanced glycation end products and improve renal damage in a type 2 diabetic nephropathy rat model. J Am Soc Nephrol 2003, 14:1212–1222.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Experimental Diabetes and Aging, The Mount Sinai School of Medicine, One Gustave Levy Place, Box 1640, 10029, New York, NY, USA

    Melpomeni Peppa MD, Jaime Uribarri MD & Helen Vlassara MD

Authors
  1. Melpomeni Peppa MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jaime Uribarri MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Helen Vlassara MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Peppa, M., Uribarri, J. & Vlassara, H. The role of advanced glycation end products in the development of atherosclerosis. Curr Diab Rep 4, 31–36 (2004). https://doi.org/10.1007/s11892-004-0008-6

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11892-004-0008-6

Keywords

Search

Navigation