Download PDF
Int J Angiol 2016; 25(02): 110-116
DOI: 10.1055/s-0035-1570754
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Atherosclerosis and the Hypercholesterolemic AGE–RAGE Axis

Erick McNair
1   Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
,
Mabood Qureshi
1   Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
,
Kailash Prasad
2   Department of Physiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
,
Colin Pearce
3   Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
› Author Affiliations
Further Information

Publication History

Publication Date:
14 January 2016 (online)

    Permissions and Reprints

Abstract

Background Interaction of advanced glycation end products (AGE) with the receptor for advanced glycation end products (RAGE) has been implicated in the pathogenesis of atherosclerosis. Soluble receptors for advanced glycation end products (sRAGE) act as a decoy for AGE by competing with RAGE and suppressing developing atherosclerosis. Hypercholesterolemia and the oxidative stress are known factors involved in atherosclerosis. High-density lipoprotein cholesterol (HDL-C) is known to exert a protective effect against the development of atherosclerosis.

We hypothesize that hypercholesterolemia-induced atherosclerosis may be mediated through the AGE–RAGE axis.

Objectives Two objectives to be determined are: (1) if hypercholesterolemia is positively correlated with serum AGE, AGE/sRAGE, and malondialdehyde (MDA: a marker for oxidative stress) and (2) if the protective effect of HDL-C is positively associated with serum sRAGE and negatively correlated with the levels of AGE and AGE/sRAGE.

Methods Measurement of serum lipid levels from 100 patients allowed the separation into two groups (hypercholesterolemic and normocholesterolemic). Measurements of serum levels of AGE, sRAGE, and MDA were performed.

Results Serum levels of sRAGE were lower, while the levels of AGE and AGE/sRAGE were higher in hypercholesterolemic subjects as compared with normocholesterolemic subjects. sRAGE levels are positively correlated with HDL, while they are negatively correlated with low-density lipoprotein, triglycerides, total cholesterol, and MDA in hypercholesterolemic subjects.

Conclusions Hypercholesterolemia is positively correlated with serum AGE, AGE/sRAGE, and MDA. The effect of HDL-C may be due to increases in sRAGE and decreases in the levels of AGE and AGE/sRAGE. Hypercholesterolemia-induced atherosclerosis may be mediated through the AGE–RAGE axis; however, more research must be conducted.

Keywords

atherosclerosis - advanced glycation end product - hypercholesterolemia - oxidative stress - coronary artery
 

  • References

  • 1 Prasad K, Kalra J. Oxygen free radicals and hypercholesterolemic atherosclerosis: effect of vitamin E. Am Heart J 1993; 125 (4) 958-973
    CrossrefPubMedGoogle Scholar
  • 2 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
  • 3 Steinberg D. Antioxidants in the prevention of human atherosclerosis. Summary of the proceedings of a National Heart, Lung, and Blood Institute Workshop: September 5-6, 1991, Bethesda, Maryland. Circulation 1992; 85 (6) 2337-2344
    CrossrefPubMedGoogle Scholar
  • 4 Prasad K. Pathophysiology of atherosclerosis. In: Chang JB, Olsen ER, Prasad K, Sumpio BE, eds. Textbook of Angiology. New York, NY: Springer-Verlag; 2003: 85
    Google Scholar
  • 5 Warnholtz A, Wendt M, August M, Münzel T. Clinical aspects of reactive oxygen and nitrogen species. Biochem Soc Symp 2004; (71) 121-133
    PubMedGoogle Scholar
  • 6 White CR, Darley-Usmar V, Berrington WR , et al. Circulating plasma xanthine oxidase contributes to vascular dysfunction in hypercholesterolemic rabbits. Proc Natl Acad Sci U S A 1996; 93 (16) 8745-8749
    CrossrefPubMedGoogle Scholar
  • 7 Liu HR, Tao L, Gao E , et al. Rosiglitazone inhibits hypercholesterolaemia-induced myeloperoxidase upregulation—a novel mechanism for the cardioprotective effects of PPAR agonists. Cardiovasc Res 2009; 81 (2) 344-352
    PubMedGoogle Scholar
  • 8 Zhu X, Lee JY, Timmins JM , et al. Increased cellular free cholesterol in macrophage-specific Abca1 knock-out mice enhances pro-inflammatory response of macrophages. J Biol Chem 2008; 283 (34) 22930-22941
    CrossrefPubMedGoogle Scholar
  • 9 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 (4) 462-472
    CrossrefPubMedGoogle Scholar
  • 10 Sunahori K, Yamamura M, Yamana J, Takasugi K, Kawashima M, Makino H. Increased expression of receptor for advanced glycation end products by synovial tissue macrophages in rheumatoid arthritis. Arthritis Rheum 2006; 54 (1) 97-104
    CrossrefPubMedGoogle Scholar
  • 11 Basta G, Schmidt AM, De Caterina R. Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovasc Res 2004; 63 (4) 582-592
    CrossrefPubMedGoogle Scholar
  • 12 Sakaguchi T, Yan SF, Yan SD , et al. Central role of RAGE-dependent neointimal expansion in arterial restenosis. J Clin Invest 2003; 111 (7) 959-972
    CrossrefPubMedGoogle Scholar
  • 13 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
  • 14 Yan SD, Schmidt AM, Anderson GM , et al. Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J Biol Chem 1994; 269 (13) 9889-9897
    PubMedGoogle Scholar
  • 15 Schmidt A, Hori O, Chen J , et al. Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes. J Clin Invest 1995; 96: 1395-1403
    CrossrefPubMedGoogle Scholar
  • 16 Laitinen TT, Pahkala K, Magnussen CG , et al. Lifetime measures of ideal cardiovascular health and their association with subclinical atherosclerosis: The Cardiovascular Risk in Young Finns Study. Int J Cardiol 2015; 185: 186-191
    CrossrefPubMedGoogle Scholar
  • 17 Prasad K. Dietary flax seed in prevention of hypercholesterolemic atherosclerosis. Atherosclerosis 1997; 132 (1) 69-76
    CrossrefPubMedGoogle Scholar
  • 18 Devangelio E, Santilli F, Formoso G , et al. Soluble RAGE in type 2 diabetes: association with oxidative stress. Free Radic Biol Med 2007; 43 (4) 511-518
    CrossrefPubMedGoogle Scholar
  • 19 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
  • 20 Hoffmann JA, Kafatos FC, Janeway CA, Ezekowitz RA. Phylogenetic perspectives in innate immunity. Science 1999; 284 (5418) 1313-1318
    CrossrefPubMedGoogle Scholar
  • 21 Bierhaus A, Chevion S, Chevion M , et al. Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells. Diabetes 1997; 46 (9) 1481-1490
    CrossrefPubMedGoogle Scholar
  • 22 Bierhaus A, Humpert PM, Morcos M , et al. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med (Berl) 2005; 83 (11) 876-886
    CrossrefPubMedGoogle Scholar
  • 23 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 (5) E685-E694
    PubMedGoogle Scholar
  • 24 Prasad K, Lee P. Suppression of hypercholesterolemic atherosclerosis by pentoxifylline and its mechanism. Atherosclerosis 2007; 192 (2) 313-322
    CrossrefPubMedGoogle Scholar
  • 25 Prasad K. A study on regression of hypercholesterolemic atherosclerosis in rabbits by flax lignan complex. J Cardiovasc Pharmacol Ther 2007; 12 (4) 304-313
    CrossrefPubMedGoogle Scholar
  • 26 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285 (19) 2486-2497
    CrossrefPubMedGoogle Scholar
  • 27 Luo X, Jiang L, Du B. A comparison of different diagnostic criteria of acute kidney injury in critically ill patients. Crit Care Res 2014; 18: 144
    PubMedGoogle Scholar
  • 28 Prasad K, McNair ED, Caspar-Bell G, Mabood Qureshi A. Vitamin E does not regress hypercholesterolemia-induced oxidative stress in heart. Mol Cell Biochem 2014; 391 (1–2) 211-216
    CrossrefPubMedGoogle Scholar
  • 29 Santilli F, Bucciarelli L, Noto D , et al. Decreased plasma soluble RAGE in patients with hypercholesterolemia: effects of statins. Free Radic Biol Med 2007; 43 (9) 1255-1262
    CrossrefPubMedGoogle Scholar
  • 30 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
  • 31 Santilli F, Vazzana N, Bucciarelli LG, Davì G. Soluble forms of RAGE in human diseases: clinical and therapeutical implications. Curr Med Chem 2009; 16 (8) 940-952
    CrossrefPubMedGoogle Scholar
  • 32 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 (9) 1025-1031
    CrossrefPubMedGoogle Scholar
  • 33 Basta G, Sironi AM, Lazzerini G , et al. Circulating soluble receptor for advanced glycation end products is inversely associated with glycemic control and S100A12 protein. J Clin Endocrinol Metab 2006; 91 (11) 4628-4634
    CrossrefPubMedGoogle Scholar
  • 34 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 (4) 187-192
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 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 (1) 238-243
    CrossrefPubMedGoogle Scholar
  • 36 Goova MT, Li J, Kislinger T , et al. Blockade of receptor for advanced glycation end-products restores effective wound healing in diabetic mice. Am J Pathol 2001; 159 (2) 513-525
    CrossrefPubMedGoogle Scholar
  • 37 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
  • 38 Prasad K, McNair ED, Qureshi AM, Casper-Bell G. Vitamin E slows the progression of hypercholesterolemia-induced oxidative stress in heart, liver and kidney. Mol Cell Biochem 2012; 368 (1–2) 181-187
    CrossrefPubMedGoogle Scholar
  • 39 Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest 1993; 91 (6) 2546-2551
    CrossrefPubMedGoogle Scholar
  • 40 Küçükgergin C, Aydin AF, Ozdemirler-Erata G, Mehmetçik G, Koçak-Toker N, Uysal M. Effect of artichoke leaf extract on hepatic and cardiac oxidative stress in rats fed on high cholesterol diet. Biol Trace Elem Res 2010; 135 (1–3) 264-274
    CrossrefPubMedGoogle Scholar
  • 41 Bierhaus A, Hofmann MA, Ziegler R, Nawroth PP. AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept. Cardiovasc Res 1998; 37 (3) 586-600
    CrossrefPubMedGoogle Scholar
  • 42 Schmidt AM, Yan SD, Yan SF, Stern DM. The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses. J Clin Invest 2001; 108 (7) 949-955
    CrossrefPubMedGoogle Scholar
  • 43 Hudson BI, Carter AM, Harja E , et al. Identification, classification, and expression of RAGE gene splice variants. FASEB J 2008; 22 (5) 1572-1580
    CrossrefPubMedGoogle Scholar
  • 44 Vazzana N, Santilli F, Cuccurullo C, Davì G. Soluble forms of RAGE in internal medicine. Intern Emerg Med 2009; 4 (5) 389-401
    CrossrefPubMedGoogle Scholar
  • 45 Raucci A, Cugusi S, Antonelli A , et al. A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10). FASEB J 2008; 22 (10) 3716-3727
    CrossrefPubMedGoogle Scholar
  • 46 Zhang L, Bukulin M, Kojro E , et al. Receptor for advanced glycation end products is subjected to protein ectodomain shedding by metalloproteinases. J Biol Chem 2008; 283 (51) 35507-35516
    CrossrefPubMedGoogle Scholar
  • 47 Parkin E, Harris B. A disintegrin and metalloproteinase (ADAM)-mediated ectodomain shedding of ADAM10. J Neurochem 2009; 108 (6) 1464-1479
    CrossrefPubMedGoogle Scholar