Download PDF
Int J Angiol 2020; 29(03): 156-167
DOI: 10.1055/s-0040-1710045
Review Article

AGE-RAGE Axis in the Pathophysiology of Chronic Lower Limb Ischemia and a Novel Strategy for Its Treatment

Kailash Prasad
1   Department of Physiology (APP), College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
,
Kalpana K. Bhanumathy
2   Division of Oncology, Cancer Cluster Unit, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
› Author Affiliations
› Further Information
   Permissions and Reprints

Abstract

This review focuses on the role of advanced glycation end products (AGEs) and its cell receptor (RAGE) and soluble receptor (sRAGE) in the pathogenesis of chronic lower limb ischemia (CLLI) and its treatment. CLLI is associated with atherosclerosis in lower limb arteries. AGE-RAGE axis which comprises of AGE, RAGE, and sRAGE has been implicated in atherosclerosis and restenosis. It may be involved in atherosclerosis of lower limb resulting in CLLI. Serum and tissue levels of AGE, and expression of RAGE are elevated, and the serum levels of sRAGE are decreased in CLLI. It is known that AGE, and AGE-RAGE interaction increase the generation of various atherogenic factors including reactive oxygen species, nuclear factor-kappa B, cell adhesion molecules, cytokines, monocyte chemoattractant protein-1, granulocyte macrophage-colony stimulating factor, and growth factors. sRAGE acts as antiatherogenic factor because it reduces the generation of AGE-RAGE-induced atherogenic factors. Treatment of CLLI should be targeted at lowering AGE levels through reduction of dietary intake of AGE, prevention of AGE formation and degradation of AGE, suppression of RAGE expression, blockade of AGE-RAGE binding, elevation of sRAGE by upregulating sRAGE expression, and exogenous administration of sRAGE, and use of antioxidants. In conclusion, AGE-RAGE stress defined as a shift in the balance between stressors (AGE, RAGE) and antistressor (sRAGE) in favor of stressors, initiates the development of atherosclerosis resulting in CLLI. Treatment modalities would include reduction of AGE levels and RAGE expression, RAGE blocker, elevation of sRAGE, and antioxidants for prevention, regression, and slowing of progression of CLLI.

Keywords

advanced glycation end products (AGE) - cell receptor for AGE - soluble receptor for AGE - AGE-RAGE stress - chronic lower limb ischemia - atherosclerosis - treatment of chronic lower limb ischemia

Disclosure

None.




Publication History

Article published online:
14 May 2020

© 2020. Thieme. All rights reserved.

Thieme Medical Publishers
333 Seventh Avenue, New York, NY 10001, USA.

 

  • References

  • 1 Creager MA, Kaufman JA, Conte MS. Clinical practice. Acute limb ischemia. N Engl J Med 2012; 366 (23) 2198-2206
    CrossrefPubMedGoogle Scholar
  • 2 Varu VN, Hogg ME, Kibbe MR. Critical limb ischemia. J Vasc Surg 2010; 51 (01) 230-241
    CrossrefPubMedGoogle Scholar
  • 3 Prasad K. Pathophysiology of Atherosclerosis. New York, NY: Springer Verlag; 2000: 85-105
    Google Scholar
  • 4 Allison MA, Ho E, Denenberg JO. , et al. Ethnic-specific prevalence of peripheral arterial disease in the United States. Am J Prev Med 2007; 32 (04) 328-333
    CrossrefPubMedGoogle Scholar
  • 5 Fowkes FG, Rudan D, Rudan I. , et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 2013; 382 (9901): 1329-1340
    CrossrefPubMedGoogle Scholar
  • 6 Baser O, Verpillat P, Gabriel S. , et al. Prevalence, incidence, and outcomes of critical limb ischemia in the US Medicare population. Vsc Dis Management 2013; 10: E26-E36
    PubMedGoogle Scholar
  • 7 Zhou Z, Wang K, Penn MS. , et al. Receptor for AGE (RAGE) mediates neointimal formation in response to arterial injury. Circulation 2003; 107 (17) 2238-2243
    CrossrefPubMedGoogle Scholar
  • 8 Sakaguchi T, Yan SF, Yan SD. , et al. Central role of RAGE-dependent neointimal expansion in arterial restenosis. J Clin Invest 2003; 111 (07) 959-972
    CrossrefPubMedGoogle Scholar
  • 9 Wendt TM, Bucciarelli LG, Lu X. , et al. Accelerated atherosclerosis and vascular inflammation develop in apo-E null mice with type 2 diabetes. Circulation 2000; 102: II-231
    CrossrefPubMedGoogle Scholar
  • 10 McNair ED, Wells CR, Qureshi AM. , et al. Low levels of soluble receptor for advanced glycation end products in non-ST elevation myocardial infarction patients. Int J Angiol 2009; 18 (04) 187-192
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 McNair ED, Wells CR, Mabood Qureshi A. , et al. Soluble receptors for advanced glycation end products (sRAGE) as a predictor of restenosis following percutaneous coronary intervention. Clin Cardiol 2010; 33 (11) 678-685
    CrossrefPubMedGoogle Scholar
  • 12 Bucala R, Cerami A. Advanced glycosylation: chemistry, biology, and implications for diabetes and aging. Adv Pharmacol 1992; 23: 1-34
    CrossrefPubMedGoogle Scholar
  • 13 Thorpe SR, Baynes JW. Maillard reaction products in tissue proteins: new products and new perspectives. Amino Acids 2003; 25 (3-4): 275-281
    CrossrefPubMedGoogle Scholar
  • 14 Tam XH, Shiu SW, Leng L, Bucala R, Betteridge DJ, Tan KC. Enhanced expression of receptor for advanced glycation end-products is associated with low circulating soluble isoforms of the receptor in type 2 diabetes. Clin Sci (Lond) 2011; 120 (02) 81-89
    CrossrefPubMedGoogle Scholar
  • 15 Yonekura H, Yamamoto Y, Sakurai S. , et al. Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury. Biochem J 2003; 370 (Pt 3): 1097-1109
    CrossrefPubMedGoogle Scholar
  • 16 Wautier MP, Chappey O, Corda S, Stern DM, Schmidt AM, Wautier JL. Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am J Physiol Endocrinol Metab 2001; 280 (05) E685-E694
    CrossrefPubMedGoogle Scholar
  • 17 Gloire G, Legrand-Poels S, Piette J. NF-kappaB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol 2006; 72 (11) 1493-1505
    CrossrefPubMedGoogle Scholar
  • 18 Reznikov LL, Waksman J, Azam T. , et al. Effect of advanced glycation end products on endotoxin-induced TNF-alpha, IL-1beta and IL-8 in human peripheral blood mononuclear cells. Clin Nephrol 2004; 61 (05) 324-336
    CrossrefPubMedGoogle Scholar
  • 19 Stassen M, Müller C, Arnold M. , et al. IL-9 and IL-13 production by activated mast cells is strongly enhanced in the presence of lipopolysaccharide: NF-κ B is decisively involved in the expression of IL-9. J Immunol 2001; 166 (07) 4391-4398
    CrossrefPubMedGoogle Scholar
  • 20 Mohammed AM, Syeda K, Hadden T, Kowluru A. Upregulation of phagocyte-like NADPH oxidase by cytokines in pancreatic beta-cells: attenuation of oxidative and nitrosative stress by 2-bromopalmitate. Biochem Pharmacol 2013; 85 (01) 109-114
    CrossrefPubMedGoogle Scholar
  • 21 Yang D, Elner SG, Bian ZM, Till GO, Petty HR, Elner VM. Pro-inflammatory cytokines increase reactive oxygen species through mitochondria and NADPH oxidase in cultured RPE cells. Exp Eye Res 2007; 85 (04) 462-472
    CrossrefPubMedGoogle Scholar
  • 22 Prasad K, Tiwari S. Therapeutic interventions for advanced glycation-end products and its receptor- mediated cardiovascular disease. Curr Pharm Des 2017; 23 (06) 937-943
    CrossrefPubMedGoogle Scholar
  • 23 Wendt T, Harja E, Bucciarelli L. , et al. RAGE modulates vascular inflammation and atherosclerosis in a murine model of type 2 diabetes. Atherosclerosis 2006; 185 (01) 70-77
    CrossrefPubMedGoogle Scholar
  • 24 Prasad K, Mishra M. AGE-RAGE stress, stressors, and antistressors in health and disease. Int J Angiol 2018; 27 (01) 1-12
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Hansen LM, Gupta D, Joseph G, Weiss D, Taylor WR. The receptor for advanced glycation end products impairs collateral formation in both diabetic and non-diabetic mice. Lab Invest 2017; 97 (01) 34-42
    CrossrefPubMedGoogle Scholar
  • 26 Tamarat R, Silvestre JS, Huijberts M. , et al. Blockade of advanced glycation end-product formation restores ischemia-induced angiogenesis in diabetic mice. Proc Natl Acad Sci U S A 2003; 100 (14) 8555-8560
    CrossrefPubMedGoogle Scholar
  • 27 Da Moura Semedo C, Webb M, Waller H, Khunti K, Davies M. Skin autofluorescence, a non-invasive marker of advanced glycation end products: clinical relevance and limitations. Postgrad Med J 2017; 93 (1099): 289-294
    CrossrefPubMedGoogle Scholar
  • 28 de Vos LC, Noordzij MJ, Mulder DJ. , et al. Skin autofluorescence as a measure of advanced glycation end products deposition is elevated in peripheral artery disease. Arterioscler Thromb Vasc Biol 2013; 33 (01) 131-138
    CrossrefPubMedGoogle Scholar
  • 29 de Vos LC, Boersema J, Mulder DJ, Smit AJ, Zeebregts CJ, Lefrandt JD. Skin autofluorescence as a measure of advanced glycation end products deposition predicts 5-year amputation in patients with peripheral artery disease. Arterioscler Thromb Vasc Biol 2015; 35 (06) 1532-1537
    CrossrefPubMedGoogle Scholar
  • 30 Noordzij MJ, Lefrandt JD, Loeffen EA. , et al. Skin autofluorescence is increased in patients with carotid artery stenosis and peripheral artery disease. Int J Cardiovasc Imaging 2012; 28 (02) 431-438
    CrossrefPubMedGoogle Scholar
  • 31 Nin JW, Jorsal A, Ferreira I. , et al. Higher plasma levels of advanced glycation end products are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes: a 12-year follow-up study. Diabetes Care 2011; 34 (02) 442-447
    CrossrefPubMedGoogle Scholar
  • 32 Lapolla A, Piarulli F, Sartore G. , et al. Advanced glycation end products and antioxidant status in type 2 diabetic patients with and without peripheral artery disease. Diabetes Care 2007; 30 (03) 670-676
    CrossrefPubMedGoogle Scholar
  • 33 Malmstedt J, Frebelius S, Lengquist M, Jörneskog G, Wang J, Swedenborg J. The receptor for advanced glycation end products (Rage) and its ligands in plasma and infrainguinal bypass vein. Eur J Vasc Endovasc Surg 2016; 51 (04) 579-586
    CrossrefPubMedGoogle Scholar
  • 34 Prasad A, Lane JR, Tsimikas S. , et al. Plasma levels of advanced glycation end products are related to the clinical presentation and angiographic severity of symptomatic lower extremity peripheral arterial disease. Int J Angiol 2016; 25 (01) 44-53
    PubMedGoogle Scholar
  • 35 Tekabe Y, Kollaros M, Li C, Zhang G, Schmidt AM, Johnson L. Imaging receptor for advanced glycation end product expression in mouse model of hind limb ischemia. EJNMMI Res 2013; 3 (01) 37
    CrossrefPubMedGoogle Scholar
  • 36 Ritthaler U, Deng Y, Zhang Y. , et al. Expression of receptors for advanced glycation end products in peripheral occlusive vascular disease. Am J Pathol 1995; 146 (03) 688-694
    PubMedGoogle Scholar
  • 37 Kim BH, Ko YG, Kim SH. , et al. Suppression of receptor for advanced glycation end products improves angiogenic responses to ischemia in diabetic mouse hindlimb ischemia model. ISRN Vascular Medicine 2013; 1-7
    CrossrefPubMedGoogle Scholar
  • 38 Falcone C, Bozzini S, Guasti L. , et al. Soluble RAGE plasma levels in patients with coronary artery disease and peripheral artery disease. ScientificWorldJournal 2013; 2013: 584504
    CrossrefPubMedGoogle Scholar
  • 39 Bucala R, Makita Z, Vega G. , et al. Modification of low density lipoprotein by advanced glycation end products contributes to the dyslipidemia of diabetes and renal insufficiency. Proc Natl Acad Sci U S A 1994; 91 (20) 9441-9445
    CrossrefPubMedGoogle Scholar
  • 40 Sutton G, Pugh D, Dhaun N. Developments in the role of endothelin-1 in atherosclerosis: a potential therapeutic target?. Am J Hypertens 2019; 32 (09) 813-815
    CrossrefPubMedGoogle Scholar
  • 41 Chang JB, Chu NF, Syu JT, Hsieh AT, Hung YR. Advanced glycation end products (AGEs) in relation to atherosclerotic lipid profiles in middle-aged and elderly diabetic patients. Lipids Health Dis 2011; 10: 228
    CrossrefPubMedGoogle Scholar
  • 42 Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 1988; 318 (20) 1315-1321
    CrossrefPubMedGoogle Scholar
  • 43 Brownlee M, Vlassara H, Cerami A. Nonenzymatic glycosylation products on collagen covalently trap low-density lipoprotein. Diabetes 1985; 34 (09) 938-941
    CrossrefPubMedGoogle Scholar
  • 44 Brownlee M, Vlassara H, Kooney A, Ulrich P, Cerami A. Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking. Science 1986; 232 (4758): 1629-1632
    CrossrefPubMedGoogle Scholar
  • 45 Bucala R, Makita Z, Koschinsky T, Cerami A, Vlassara H. Lipid advanced glycosylation: pathway for lipid oxidation in vivo. Proc Natl Acad Sci U S A 1993; 90 (14) 6434-6438
    CrossrefPubMedGoogle Scholar
  • 46 Bucala R, Cerami A, Vlassara H. Advanced glycation end products in diabetic complications. Diabetes Rev (Alex) 1995; 3: 258-268
    PubMedGoogle Scholar
  • 47 Ren X, Ren L, Wei Q, Shao H, Chen L, Liu N. Advanced glycation end-products decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells. Cardiovasc Diabetol 2017; 16 (01) 52
    CrossrefPubMedGoogle Scholar
  • 48 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 (02) 432-438
    CrossrefPubMedGoogle Scholar
  • 49 Xu B, Chibber R, Ruggiero D, Kohner E, Ritter J, Ferro A. Impairment of vascular endothelial nitric oxide synthase activity by advanced glycation end products. FASEB J 2003; 17 (10) 1289-1291
    CrossrefPubMedGoogle Scholar
  • 50 Rojas A, Romay S, González D, Herrera B, Delgado R, Otero K. Regulation of endothelial nitric oxide synthase expression by albumin-derived advanced glycosylation end products. Circ Res 2000; 86 (03) E50-E54
    CrossrefPubMedGoogle Scholar
  • 51 Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation 2006; 114 (06) 597-605
    CrossrefPubMedGoogle Scholar
  • 52 Hogan M, Cerami A, Bucala R. Advanced glycosylation endproducts block the antiproliferative effect of nitric oxide. Role in the vascular and renal complications of diabetes mellitus. J Clin Invest 1992; 90 (03) 1110-1115
    CrossrefPubMedGoogle Scholar
  • 53 Matsui T, Oda E, Higashimoto Y, Yamagishi S. Glyceraldehyde-derived pyridinium (GLAP) evokes oxidative stress and inflammatory and thrombogenic reactions in endothelial cells via the interaction with RAGE. Cardiovasc Diabetol 2015; 14: 1-10
    CrossrefPubMedGoogle Scholar
  • 54 Quehenberger P, Bierhaus A, Fasching P. , et al. Endothelin 1 transcription is controlled by nuclear factor-kappaB in AGE-stimulated cultured endothelial cells. Diabetes 2000; 49 (09) 1561-1570
    CrossrefPubMedGoogle Scholar
  • 55 Haberland ME, Fless GM, Scanu AM, Fogelman AM. Malondialdehyde modification of lipoprotein(a) produces avid uptake by human monocyte-macrophages. J Biol Chem 1992; 267 (06) 4143-4151
    CrossrefPubMedGoogle Scholar
  • 56 Makita T, Tanaka A, Numano F. Effect of glycated low density lipoprotein on smooth muscle cell proliferation. Int Angiol 1999; 18 (04) 331-334
    PubMedGoogle Scholar
  • 57 Horiuchi S, Sakamoto Y, Sakai M. Scavenger receptors for oxidized and glycated proteins. Amino Acids 2003; 25 (3-4): 283-292
    CrossrefPubMedGoogle Scholar
  • 58 Brown BE, Dean RT, Davies MJ. Glycation of low-density lipoproteins by methylglyoxal and glycolaldehyde gives rise to the in vitro formation of lipid-laden cells. Diabetologia 2005; 48 (02) 361-369
    CrossrefPubMedGoogle Scholar
  • 59 Hofmann MA, Drury S, Fu C. , et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 1999; 97 (07) 889-901
    CrossrefPubMedGoogle Scholar
  • 60 Basta G, Lazzerini G, Massaro M. , et al. Advanced glycation end products activate endothelium through signal-transduction receptor RAGE: a mechanism for amplification of inflammatory responses. Circulation 2002; 105 (07) 816-822
    CrossrefPubMedGoogle Scholar
  • 61 Siebenlist U, Franzoso G, Brown K. Structure, regulation and function of NF-κ B. Annu Rev Cell Biol 1994; 10: 405-455
    CrossrefPubMedGoogle Scholar
  • 62 Anrather J, Racchumi G, Iadecola C. NF-kappaB regulates phagocytic NADPH oxidase by inducing the expression of gp91phox. J Biol Chem 2006; 281 (09) 5657-5667
    CrossrefPubMedGoogle Scholar
  • 63 Kislinger T, Tanji N, Wendt T. , et al. Receptor for advanced glycation end products mediates inflammation and enhanced expression of tissue factor in vasculature of diabetic apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol 2001; 21 (06) 905-910
    CrossrefPubMedGoogle Scholar
  • 64 Matsui T, Yamagishi S, Ueda S. , et al. Telmisartan, an angiotensin II type 1 receptor blocker, inhibits advanced glycation end-product (AGE)-induced monocyte chemoattractant protein-1 expression in mesangial cells through downregulation of receptor for AGEs via peroxisome proliferator-activated receptor-gamma activation. J Int Med Res 2007; 35 (04) 482-489
    CrossrefPubMedGoogle Scholar
  • 65 Yamagishi S, Inagaki Y, Okamoto T. , et al. Advanced glycation end product-induced apoptosis and overexpression of vascular endothelial growth factor and monocyte chemoattractant protein-1 in human-cultured mesangial cells. J Biol Chem 2002; 277 (23) 20309-20315
    CrossrefPubMedGoogle Scholar
  • 66 Gu L, Hagiwara S, Fan Q. , et al. Role of receptor for advanced glycation end-products and signalling events in advanced glycation end-product-induced monocyte chemoattractant protein-1 expression in differentiated mouse podocytes. Nephrol Dial Transplant 2006; 21 (02) 299-313
    CrossrefPubMedGoogle Scholar
  • 67 Sasaki T, Horiuchi S, Yamazaki M, Yui S. Induction of GM-CSF production of macrophages by advanced glycation end products of the Maillard reaction. Biosci Biotechnol Biochem 1999; 63 (11) 2011-2013
    CrossrefPubMedGoogle Scholar
  • 68 Kirstein M, Brett J, Radoff S, Ogawa S, Stern D, Vlassara H. Advanced protein glycosylation induces transendothelial human monocyte chemotaxis and secretion of platelet-derived growth factor: role in vascular disease of diabetes and aging. Proc Natl Acad Sci U S A 1990; 87 (22) 9010-9014
    CrossrefPubMedGoogle Scholar
  • 69 Kirstein M, Aston C, Hintz R, Vlassara H. Receptor-specific induction of insulin-like growth factor I in human monocytes by advanced glycosylation end product-modified proteins. J Clin Invest 1992; 90 (02) 439-446
    CrossrefPubMedGoogle Scholar
  • 70 Schmidt AM, Yan SD, Brett J, Mora R, Nowygrod R, Stern D. Regulation of human mononuclear phagocyte migration by cell surface-binding proteins for advanced glycation end products. J Clin Invest 1993; 91 (05) 2155-2168
    CrossrefPubMedGoogle Scholar
  • 71 Miyata T, Inagi R, Iida Y. , et al. Involvement of β 2-microglobulin modified with advanced glycation end products in the pathogenesis of hemodialysis-associated amyloidosis. Induction of human monocyte chemotaxis and macrophage secretion of tumor necrosis factor-α and interleukin-1. J Clin Invest 1994; 93 (02) 521-528
    CrossrefPubMedGoogle Scholar
  • 72 Sakata N, Meng J, Takebayashi S. Effects of advanced glycation end products on the proliferation and fibronectin production of smooth muscle cells. J Atheroscler Thromb 2000; 7 (03) 169-176
    CrossrefPubMedGoogle Scholar
  • 73 Higashi T, Sano H, Saishoji T. , et al. The receptor for advanced glycation end products mediates the chemotaxis of rabbit smooth muscle cells. Diabetes 1997; 46 (03) 463-472
    CrossrefPubMedGoogle Scholar
  • 74 Wolf YG, Rasmussen LM, Ruoslahti E. Antibodies against transforming growth factor-β 1 suppress intimal hyperplasia in a rat model. J Clin Invest 1994; 93 (03) 1172-1178
    CrossrefPubMedGoogle Scholar
  • 75 Steinberg D. Antioxidants and atherosclerosis. A current assessment. Circulation 1991; 84 (03) 1420-1425
    CrossrefPubMedGoogle Scholar
  • 76 Aronson D, Rayfield EJ. How hyperglycemia promotes atherosclerosis: molecular mechanisms. Cardiovasc Diabetol 2002; 1: 1
    CrossrefPubMedGoogle Scholar
  • 77 Prasad K. The pathophysiology of atherosclerosis. In: Chang JB. , ed. Textbook of Angiology. New York, NY: Springer; 2000: 17-46
    Google Scholar
  • 78 Nowak WN, Deng J, Ruan XZ, Xu Q. Reactive oxygen species generation and atherosclerosis. Arterioscler Thromb Vasc Biol 2017; 37 (05) e41-e52
    CrossrefPubMedGoogle Scholar
  • 79 Kattoor AJ, Pothineni NVK, Palagiri D, Mehta JL. Oxidative stress in atherosclerosis. Curr Atheroscler Rep 2017; 19 (11) 42
    CrossrefPubMedGoogle Scholar
  • 80 Weisenberger J. Foods High in AGEs. Accessed 2014 at: http://wwwdiabetesforecastorg/2014/11-nov/foods-high-in-ageshtml
    Google Scholar
  • 81 Uribarri J, Woodruff S, Goodman S. , et al. Advanced glycation end products in foods and a practical guide to their reduction in the diet. J Am Diet Assoc 2010; 110 (06) 911-16.e12
    CrossrefPubMedGoogle Scholar
  • 82 Uribarri J, Cai W, Sandu O, Peppa M, Goldberg T, Vlassara H. Diet-derived advanced glycation end products are major contributors to the body's AGE pool and induce inflammation in healthy subjects. Ann N Y Acad Sci 2005; 1043: 461-466
    CrossrefPubMedGoogle Scholar
  • 83 Prasad K, Dhar I, Caspar-Bell G. Role of advanced glycation end products and its receptors in the pathogenesis of cigarette smoke-induced cardiovascular disease. Int J Angiol 2015; 24 (02) 75-80
    PubMedGoogle Scholar
  • 84 Kondoh Y, Kawase M, Ohmori S. D-lactate concentrations in blood, urine and sweat before and after exercise. Eur J Appl Physiol Occup Physiol 1992; 65 (01) 88-93
    CrossrefPubMedGoogle Scholar
  • 85 Salama ME, El-Damarawi MA, Salama AF. A comparison between the impact of two different exercise protocols on advanced glycation end products in type 2 diabetic rats. Life Sci J 2013; 10 (03) 860-869
    PubMedGoogle Scholar
  • 86 Goon JA, Aini AH, Musalmah M, Anum MY, Nazaimoon WM, Ngah WZ. Effect of Tai Chi exercise on DNA damage, antioxidant enzymes, and oxidative stress in middle-age adults. J Phys Act Health 2009; 6 (01) 43-54
    CrossrefPubMedGoogle Scholar
  • 87 Ramful D, Tarnus E, Rondeau P, Da Silva CR, Bahorun T, Bourdon E. Citrus fruit extracts reduce advanced glycation end products (AGEs)- and H2O2-induced oxidative stress in human adipocytes. J Agric Food Chem 2010; 58 (20) 11119-11129
    CrossrefPubMedGoogle Scholar
  • 88 Liu W, Ma H, Frost L, Yuan T, Dain JA, Seeram NP. Pomegranate phenolics inhibit formation of advanced glycation endproducts by scavenging reactive carbonyl species. Food Funct 2014; 5 (11) 2996-3004
    CrossrefPubMedGoogle Scholar
  • 89 Hammes HP, Du X, Edelstein D. , et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 2003; 9 (03) 294-299
    CrossrefPubMedGoogle Scholar
  • 90 Metz TO, Alderson NL, Thorpe SR, Baynes JW. Pyridoxamine, an inhibitor of advanced glycation and lipoxidation reactions: a novel therapy for treatment of diabetic complications. Arch Biochem Biophys 2003; 419 (01) 41-49
    CrossrefPubMedGoogle Scholar
  • 91 Subratty AH, Aukburally N, Jowaheer V. , et al. Vitamin C and urea inhibit the formation of advanced glycation end products in vitro. Nutr Food Sci 2010; 40 (05) 456-465
    CrossrefPubMedGoogle Scholar
  • 92 Salum E, Kals J, Kampus P. , et al. Vitamin D reduces deposition of advanced glycation end-products in the aortic wall and systemic oxidative stress in diabetic rats. Diabetes Res Clin Pract 2013; 100 (02) 243-249
    CrossrefPubMedGoogle Scholar
  • 93 Baragetti I, Furiani S, Vettoretti S. , et al. Role of vitamin E-coated membrane in reducing advanced glycation end products in hemodialysis patients: a pilot study. Blood Purif 2006; 24 (04) 369-376
    CrossrefPubMedGoogle Scholar
  • 94 Ghodsi R, Kheirouri S. Carnosine and advanced glycation end products: a systematic review. Amino Acids 2018; 50 (09) 1177-1186
    CrossrefPubMedGoogle Scholar
  • 95 Menini S, Iacobini C, Ricci C. , et al. D-Carnosine octylester attenuates atherosclerosis and renal disease in ApoE null mice fed a Western diet through reduction of carbonyl stress and inflammation. Br J Pharmacol 2012; 166 (04) 1344-1356
    CrossrefPubMedGoogle Scholar
  • 96 Menini S, Iacobini C, Ricci C, Blasetti Fantauzzi C, Pugliese G. Protection from diabetes-induced atherosclerosis and renal disease by D-carnosine-octylester: effects of early vs late inhibition of advanced glycation end-products in Apoe-null mice. Diabetologia 2015; 58 (04) 845-853
    CrossrefPubMedGoogle Scholar
  • 97 Prasanna G, Saraswathi NT. Linolenic acid prevents early and advanced glycation end-products (AGEs) modification of albumin. Int J Biol Macromol 2017; 95: 121-125
    CrossrefPubMedGoogle Scholar
  • 98 Thornalley PJ. Use of aminoguanidine (Pimagedine) to prevent the formation of advanced glycation end products. Arch Biochem Biophys 2003; 419 (01) 31-40
    CrossrefPubMedGoogle Scholar
  • 99 Freedman BI, Wuerth JP, Cartwright K. , et al. Design and baseline characteristics for the aminoguanidine clinical trial in overt Type 2 diabetic nephropathy (ACTION II). Control Clin Trials 1999; 20 (05) 493-510
    CrossrefPubMedGoogle Scholar
  • 100 Abdul HM, Butterfield DA. Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and alpha-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: implications for Alzheimer's disease. Free Radic Biol Med 2007; 42 (03) 371-384
    CrossrefPubMedGoogle Scholar
  • 101 Urios P, Grigorova-Borsos AM, Sternberg M. Aspirin inhibits the formation of pentosidine, a cross-linking advanced glycation end product, in collagen. Diabetes Res Clin Pract 2007; 77 (02) 337-340
    CrossrefPubMedGoogle Scholar
  • 102 Beisswenger PJ, Howell SK, Touchette AD, Lal S, Szwergold BS. Metformin reduces systemic methylglyoxal levels in type 2 diabetes. Diabetes 1999; 48 (01) 198-202
    CrossrefPubMedGoogle Scholar
  • 103 Rahbar S, Natarajan R, Yerneni K, Scott S, Gonzales N, Nadler JL. Evidence that pioglitazone, metformin and pentoxifylline are inhibitors of glycation. Clin Chim Acta 2000; 301 (1-2): 65-77
    CrossrefPubMedGoogle Scholar
  • 104 Mizutani K, Ikeda K, Yamori Y. Resveratrol inhibits AGEs-induced proliferation and collagen synthesis activity in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats. Biochem Biophys Res Commun 2000; 274 (01) 61-67
    CrossrefPubMedGoogle Scholar
  • 105 Tang Y, Chen A. Curcumin eliminates the effect of advanced glycation end-products (AGEs) on the divergent regulation of gene expression of receptors of AGEs by interrupting leptin signaling. Lab Invest 2014; 94 (05) 503-516
    CrossrefPubMedGoogle Scholar
  • 106 Cuccurullo C, Iezzi A, Fazia ML. , et al. Suppression of RAGE as a basis of simvastatin-dependent plaque stabilization in type 2 diabetes. Arterioscler Thromb Vasc Biol 2006; 26 (12) 2716-2723
    CrossrefPubMedGoogle Scholar
  • 107 Xu L, Zang P, Feng B, Qian Q. Atorvastatin inhibits the expression of RAGE induced by advanced glycation end products on aortas in healthy Sprague-Dawley rats. Diabetol Metab Syndr 2014; 6 (01) 102
    CrossrefPubMedGoogle Scholar
  • 108 Nakamura K, Yamagishi S, Nakamura Y. , et al. Telmisartan inhibits expression of a receptor for advanced glycation end products (RAGE) in angiotensin-II-exposed endothelial cells and decreases serum levels of soluble RAGE in patients with essential hypertension. Microvasc Res 2005; 70 (03) 137-141
    CrossrefPubMedGoogle Scholar
  • 109 Fan Q, Liao J, Kobayashi M. , et al. Candesartan reduced advanced glycation end-products accumulation and diminished nitro-oxidative stress in type 2 diabetic KK/Ta mice. Nephrol Dial Transplant 2004; 19 (12) 3012-3020
    CrossrefPubMedGoogle Scholar
  • 110 Yamagishi S, Takeuchi M. Nifedipine inhibits gene expression of receptor for advanced glycation end products (RAGE) in endothelial cells by suppressing reactive oxygen species generation. Drugs Exp Clin Res 2004; 30 (04) 169-175
    PubMedGoogle Scholar
  • 111 Marx N, Walcher D, Ivanova N. , et al. Thiazolidinediones reduce endothelial expression of receptors for advanced glycation end products. Diabetes 2004; 53 (10) 2662-2668
    CrossrefPubMedGoogle Scholar
  • 112 Lin J, Tang Y, Kang Q, Feng Y, Chen A. Curcumin inhibits gene expression of receptor for advanced glycation end-products (RAGE) in hepatic stellate cells in vitro by elevating PPARγ activity and attenuating oxidative stress. Br J Pharmacol 2012; 166 (08) 2212-2227
    CrossrefPubMedGoogle Scholar
  • 113 Sabbagh MN, Agro A, Bell J, Aisen PS, Schweizer E, Galasko D. PF-04494700, an oral inhibitor of receptor for advanced glycation end products (RAGE), in Alzheimer disease. Alzheimer Dis Assoc Disord 2011; 25 (03) 206-212
    CrossrefPubMedGoogle Scholar
  • 114 Bongarzone S, Savickas V, Luzi F, Gee AD. Targeting the receptor for advanced glycation endproducts (RAGE): a medicinal chemistry perspective. J Med Chem 2017; 60 (17) 7213-7232
    CrossrefPubMedGoogle Scholar
  • 115 Burstein AH, Sabbagh M, Andrews R, Valcarce C, Dunn I, Altstiel L. Development of azeliragon, an oral small molecule antagonist of the receptor for advanced glycation endproducts, for the potential slowing of loss of cognition in mild Alzheimer's disease. J Prev Alzheimers Dis 2018; 5 (02) 149-154
    PubMedGoogle Scholar
  • 116 A phase 2 study evaluating the efficacy and safety of PF04494700 in mild to moderate Alzheimer's disease. Pfizer, Alzheimer's disease Cooperative Study (ADCS). Clinical trials.gov identifier: NCT00566397. . Accessed April 7, 2020 at: http://clinicaltrials.gov/ct2/show/NCToo566397
    Google Scholar
  • 117 Mannervik B. Molecular enzymology of the glyoxalase system. Drug Metabol Drug Interact 2008; 23 (1-2): 13-27
    CrossrefPubMedGoogle Scholar
  • 118 Xue M, Weickert MO, Qureshi S. , et al. Improved glycemic control and vascular function in overweight and obese subjects by glyoxalase 1 inducer formulation. Diabetes 2016; 65 (08) 2282-2294
    CrossrefPubMedGoogle Scholar
  • 119 Gangadhariah MH, Mailankot M, Reneker L, Nagaraj RH. Inhibition of methylglyoxal-mediated protein modification in glyoxalase I overexpressing mouse lenses. J Ophthalmol 2010; 2010: 274317
    CrossrefPubMedGoogle Scholar
  • 120 Miller AG, Smith DG, Bhat M, Nagaraj RH. Glyoxalase I is critical for human retinal capillary pericyte survival under hyperglycemic conditions. J Biol Chem 2006; 281 (17) 11864-11871
    CrossrefPubMedGoogle Scholar
  • 121 Lu C, He JC, Cai W, Liu H, Zhu L, Vlassara H. Advanced glycation endproduct (AGE) receptor 1 is a negative regulator of the inflammatory response to AGE in mesangial cells. Proc Natl Acad Sci U S A 2004; 101 (32) 11767-11772
    CrossrefPubMedGoogle Scholar
  • 122 Cai W, He JC, Zhu L, Lu C, Vlassara H. Advanced glycation end product (AGE) receptor 1 suppresses cell oxidant stress and activation signaling via EGF receptor. Proc Natl Acad Sci U S A 2006; 103 (37) 13801-13806
    CrossrefPubMedGoogle Scholar
  • 123 Cai W, He JC, Zhu L, Chen X, Striker GE, Vlassara H. AGE-receptor-1 counteracts cellular oxidant stress induced by AGEs via negative regulation of p66shc-dependent FKHRL1 phosphorylation. Am J Physiol Cell Physiol 2008; 294 (01) C145-C152
    CrossrefPubMedGoogle Scholar
  • 124 He CJ, Koschinsky T, Buenting C, Vlassara H. Presence of diabetic complications in type 1 diabetic patients correlates with low expression of mononuclear cell AGE-receptor-1 and elevated serum AGE. Mol Med 2001; 7 (03) 159-168
    CrossrefPubMedGoogle Scholar
  • 125 Nozue T, Yamagishi S-i, Takeuchi M. , et al. Effect of statins on the serum soluble form of receptor for advanced glycation end-products and its association with coronary atherosclerosis in patients with angina pectoris. IJC Metab Endocr 2014; 4: 47-52
    CrossrefPubMedGoogle Scholar
  • 126 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 (01) 173-177
    CrossrefPubMedGoogle Scholar
  • 127 Quade-Lyssy P, Kanarek AM, Baiersdörfer M, Postina R, Kojro E. Statins stimulate the production of a soluble form of the receptor for advanced glycation end products. J Lipid Res 2013; 54 (11) 3052-3061
    CrossrefPubMedGoogle Scholar
  • 128 Forbes JM, Thorpe SR, Thallas-Bonke V. , 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 (08) 2363-2372
    CrossrefPubMedGoogle Scholar
  • 129 Tan KCB, Chow WS, Tso AWK. , et al. Thiazolidinedione increases serum soluble receptor for advanced glycation end-products in type 2 diabetes. Diabetologia 2007; 50 (09) 1819-1825
    CrossrefPubMedGoogle Scholar
  • 130 Irani M, Minkoff H, Seifer DB, Merhi Z. Vitamin D increases serum levels of the soluble receptor for advanced glycation end products in women with PCOS. J Clin Endocrinol Metab 2014; 99 (05) E886-E890
    CrossrefPubMedGoogle Scholar
  • 131 Park L, Raman KG, Lee KJ. , et al. Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts. Nat Med 1998; 4 (09) 1025-1031
    CrossrefPubMedGoogle Scholar
  • 132 Tang SC, Wang YC, Li YI. , et al. Functional role of soluble receptor for advanced glycation end products in stroke. Arterioscler Thromb Vasc Biol 2013; 33 (03) 585-594
    CrossrefPubMedGoogle Scholar
  • 133 Yang X, Li Y, Li Y. , et al. Oxidative stress-mediated atherosclerosis: mechanisms and therapies. Front Physiol 2017; 8: 600
    CrossrefPubMedGoogle Scholar
  • 134 Prasad K. Reduction of serum cholesterol and hypercholesterolemic atherosclerosis in rabbits by secoisolariciresinol diglucoside isolated from flaxseed. Circulation 1999; 99 (10) 1355-1362
    CrossrefPubMedGoogle Scholar
  • 135 Prasad K, Kalra J, Lee P. Oxygen free radicals as a mechanism of hypercholesterolemic athetrosclerosis: effects of probucol. Int J Angiol 1994; 3: 100-112
    Article in Thieme ConnectPubMedGoogle Scholar
  • 136 Azen SP, Qian D, Mack WJ. , et al. Effect of supplementary antioxidant vitamin intake on carotid arterial wall intima-media thickness in a controlled clinical trial of cholesterol lowering. Circulation 1996; 94 (10) 2369-2372
    CrossrefPubMedGoogle Scholar
  • 137 Gale CR, Ashurst HE, Powers HJ, Martyn CN. Antioxidant vitamin status and carotid atherosclerosis in the elderly. Am J Clin Nutr 2001; 74 (03) 402-408
    CrossrefPubMedGoogle Scholar
  • 138 Prasad K, Kalra J. Oxygen free radicals and hypercholesterolemic atherosclerosis: effect of vitamin E. Am Heart J 1993; 125 (04) 958-973
    CrossrefPubMedGoogle Scholar
  • 139 Meydani M, Kwan P, Band M. , et al. Long-term vitamin E supplementation reduces atherosclerosis and mortality in Ldlr-/- mice, but not when fed Western style diet. Atherosclerosis 2014; 233 (01) 196-205
    CrossrefPubMedGoogle Scholar
  • 140 Saboori S, Shab-Bidar S, Speakman JR, Yousefi Rad E, Djafarian K. Effect of vitamin E supplementation on serum C-reactive protein level: a meta-analysis of randomized controlled trials. Eur J Clin Nutr 2015; 69 (08) 867-873
    CrossrefPubMedGoogle Scholar
  • 141 Myung SK, Ju W, Cho B. , et al; Korean Meta-Analysis Study Group. Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials. BMJ 2013; 346: f10
    CrossrefPubMedGoogle Scholar
  • 142 Niki E. Interaction of ascorbate and alpha-tocopherol. Ann N Y Acad Sci 1987; 498: 186-199
    CrossrefPubMedGoogle Scholar
  • 143 Mashima R, Witting PK, Stocker R. Oxidants and antioxidants in atherosclerosis. Curr Opin Lipidol 2001; 12 (04) 411-418
    CrossrefPubMedGoogle Scholar
  • 144 Witting PK, Pettersson K, Letters J, Stocker R. Anti-atherogenic effect of coenzyme Q10 in apolipoprotein E gene knockout mice. Free Radic Biol Med 2000; 29 (3-4): 295-305
    CrossrefPubMedGoogle Scholar
  • 145 Heinecke JW. Oxidants and antioxidants in the pathogenesis of atherosclerosis: implications for the oxidized low density lipoprotein hypothesis. Atherosclerosis 1998; 141 (01) 1-15
    CrossrefPubMedGoogle Scholar
  • 146 Stocker R. Dietary and pharmacological antioxidants in atherosclerosis. Curr Opin Lipidol 1999; 10 (06) 589-597
    CrossrefPubMedGoogle Scholar
  • 147 Blake GJ, Ridker PM. Novel clinical markers of vascular wall inflammation. Circ Res 2001; 89 (09) 763-771
    CrossrefPubMedGoogle Scholar
  • 148 Noguchi N, Niki E. Phenolic antioxidants: a rationale for design and evaluation of novel antioxidant drug for atherosclerosis. Free Radic Biol Med 2000; 28 (10) 1538-1546
    CrossrefPubMedGoogle Scholar
  • 149 Prasad K, Mantha SV, Kalra J, Lee P. Prevention of hypercholesterolemic atherosclerosis by garlic, an antioxidant. J Cardiovasc Pharmacol Ther 1997; 2 (04) 309-320
    CrossrefPubMedGoogle Scholar
  • 150 Cooke JP, Dzau VJ. Derangements of the nitric oxide synthase pathway, L-arginine, and cardiovascular diseases. Circulation 1997; 96 (02) 379-382
    PubMedGoogle Scholar
  • 151 Harrison DG. Cellular and molecular mechanisms of endothelial cell dysfunction. J Clin Invest 1997; 100 (09) 2153-2157
    CrossrefPubMedGoogle Scholar
  • 152 Persson F, Rossing P, Hovind P. , et al. Endothelial dysfunction and inflammation predict development of diabetic nephropathy in the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA 2) study. Scand J Clin Lab Invest 2008; 68 (08) 731-738
    CrossrefPubMedGoogle Scholar
  • 153 Khera AV, Cuchel M, de la Llera-Moya M. , et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 2011; 364 (02) 127-135
    CrossrefPubMedGoogle Scholar
  • 154 Wautier JL, Guillausseau PJ. Advanced glycation end products, their receptors and diabetic angiopathy. Diabetes Metab 2001; 27 (5 Pt 1): 535-542
    PubMedGoogle Scholar
  • 155 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 (06) 1649-1656
    PubMedGoogle Scholar
  • 156 Koyama H, Yamamoto H, Nishizawa Y. RAGE and soluble RAGE: potential therapeutic targets for cardiovascular diseases. Mol Med 2007; 13 (11-12): 625-635
    CrossrefPubMedGoogle Scholar
  • 157 Tan KC, Shiu SW, Chow WS, Leng L, Bucala R, Betteridge DJ. Association between serum levels of soluble receptor for advanced glycation end products and circulating advanced glycation end products in type 2 diabetes. Diabetologia 2006; 49 (11) 2756-2762
    CrossrefPubMedGoogle Scholar
  • 158 Challier M, Jacqueminet S, Benabdesselam O, Grimaldi A, Beaudeux JL. Increased serum concentrations of soluble receptor for advanced glycation endproducts in patients with type 1 diabetes. Clin Chem 2005; 51 (09) 1749-1750
    CrossrefPubMedGoogle Scholar
  • 159 Lin RY, Choudhury RP, Cai W. , et al. Dietary glycotoxins promote diabetic atherosclerosis in apolipoprotein E-deficient mice. Atherosclerosis 2003; 168 (02) 213-220
    CrossrefPubMedGoogle Scholar
  • 160 Boor P, Celec P, Behuliak M. , et al. Regular moderate exercise reduces advanced glycation and ameliorates early diabetic nephropathy in obese Zucker rats. Metabolism 2009; 58 (11) 1669-1677
    CrossrefPubMedGoogle Scholar
  • 161 Couppé C, Svensson RB, Grosset JF. , et al. Life-long endurance running is associated with reduced glycation and mechanical stress in connective tissue. Age (Dordr) 2014; 36 (04) 9665
    CrossrefPubMedGoogle Scholar
  • 162 Magalhaes PM, Appell HJ, Durate JA. Involvement of advanced glycation end products in the pathogenesis of diabetic complications: protective role of regular physical activity. Eur Rev Aging Phys Act 2008; 5: 17-29
    CrossrefPubMedGoogle Scholar
  • 163 Stirban A, Negrean M, Stratmann B. , et al. Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes. Diabetes Care 2006; 29 (09) 2064-2071
    CrossrefPubMedGoogle Scholar
  • 164 Dutta A, Dutta SK. Vitamin E and its role in the prevention of atherosclerosis and carcinogenesis: a review. J Am Coll Nutr 2003; 22 (04) 258-268
    CrossrefPubMedGoogle Scholar
  • 165 Salonen RM, Nyyssönen K, Kaikkonen J. , et al; Antioxidant Supplementation in Atherosclerosis Prevention Study. Six-year effect of combined vitamin C and E supplementation on atherosclerotic progression: the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study. Circulation 2003; 107 (07) 947-953
    CrossrefPubMedGoogle Scholar