Advertisement

Dietary glycotoxins promote diabetic atherosclerosis in apolipoprotein E-deficient mice

  • Reigh-Yi Lin
    Affiliations
    Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, Box 1640, One Gustave L. Levy Place, New York, NY 10029, USA
    Search for articles by this author
  • Robin P. Choudhury
    Affiliations
    Department of Surgery, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA

    Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA
    Search for articles by this author
  • Weijing Cai
    Affiliations
    Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, Box 1640, One Gustave L. Levy Place, New York, NY 10029, USA
    Search for articles by this author
  • Min Lu
    Affiliations
    Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, Box 1640, One Gustave L. Levy Place, New York, NY 10029, USA
    Search for articles by this author
  • John T. Fallon
    Affiliations
    Department of Surgery, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA

    Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA
    Search for articles by this author
  • Edward A. Fisher
    Affiliations
    Department of Surgery, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA

    Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA
    Search for articles by this author
  • Helen Vlassara
    Correspondence
    Corresponding author. Present Address: Division of Experimental Diabetes and Aging, Box # 1640, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6574, USA. Tel.: +1-212-659-1551; fax: +1-212-849-2652
    Affiliations
    Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, Box 1640, One Gustave L. Levy Place, New York, NY 10029, USA
    Search for articles by this author

      Abstract

      Hyperglycemia derived advanced glycation endproducts (AGE) have been implicated in diabetic atherosclerosis (AS) but the role of exogenous (dietary) AGE in the development of this serious complication is not known. This study evaluates the influence of diet-related AGE on AS in genetically hypercholesterolemic apolipoprotein E-deficient (apoE−/−), streptozotocin-induced diabetic mice. Diabetic and non-diabetic apoE−/− mice (6–8 weeks old) were randomized into either a standard AIN-93G chow (AGE 12 500±700 U/mg, termed high-AGE diet, H-AGE), or the same chow having four to fivefold lower AGE level (L-AGE: 2700±830 U/mg) based on ELISA. After 2 months of diabetes, compared to the diabetic mice fed standard (H-AGE) diet, the AS lesions at the aortic root of the L-AGE group were >50% smaller (0.17±0.03 vs. 0.31±0.05 mm2, P<0.05). Serum AGE were lower in the diabetic L-AGE than in the H-AGE mice (by ∼53%) (P<0.00001), as were in the non-diabetic L-AGE vs. H-AGE groups (P<0.05). No diet-related changes were noted in plasma glucose, triglycerides, or plasma cholesterol. Immunohistochemical comparisons showed markedly suppressed tissue AGE, AGE-Receptor-1, -2 and RAGE expression, reduced numbers of inflammatory cells, tissue factor, vascular cell adhesion molecule-1 and MCP-1 in the L-AGE diabetic group. The findings are supportive of an important link between dietary intake of pre-formed glycoxidation products, tissue-incorporated AGE, and diabetes-accelerated AS. The marked anti-atherogenic effects of an AGE-restricted diet in this model may provide the basis for relevant clinical studies.

      Keywords

      Abbreviations:

      AGE, advanced glycation endproducts (), AIN, American Institute of Nutrition (), apoE−/−, apolipoprotein E-deficient (), NOD, non-obese diabetic (), STZ, streptozotocin (), HDL, high density lipoprotein (), TG, triglyceride (), VCAM, vascular cell adhesion molecule (), SMC, smooth muscle cell (), CML, Nε-carboxymethyl-lysine (), MG, methylglyoxal ()
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Haffner S.M.
        • Lehto S.
        • Ronnemaa T.
        • Pyorala K.
        • Laakso M.
        Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.
        N. Eng. J. Med. 1998; 339: 229-234
      1. Ruderman N. Williamson J. Brownlee M. Hyperglycemia, diabetes and vascular disease. American Physiological Society/Oxford University Press, Oxford, UK1992
        • Massi-Benedetti M.
        • Federici M.O.
        Cardiovascular risk factors in type 2 diabetes: the role of hyperglycaemia.
        Exp. Clin. Endocrinol. Diabetes. 1999; 107: S120-S123
        • Vlassara H.
        • Bucala R.
        • Striker L.
        Pathogenic effects of advanced glycosylation: biochemical, biologic, and clinical implications for diabetes and aging.
        Lab. Invest. 1994; 70: 138-151
        • Wells-Knecht K.J.
        • Zyzak D.V.
        • Litchfield J.E.
        • Thorpe S.R.
        • Baynes J.W.
        Mechanism of autoxidative glycosylation: identification of glyoxal and arabinose as intermediates in the autoxidative modification of proteins by glucose.
        Biochemistry. 1995; 34: 3702-3709
        • Grandhee S.K.
        • Monnier V.M.
        Mechanism of formation of the Maillard protein cross-link pentosidine, glucose, fructose, and ascorbate as pentosidine precursors.
        J. Biol. Chem. 1991; 266: 11649-11653
        • Bucala R.
        • Makita Z.
        • Koschinsky T.
        • Cerami A.
        • Vlassara H.
        Lipid advanced glycosylation: pathway for lipid oxidation in vivo.
        Proc. Natl. Acad. Sci. USA. 1993; 90: 6434-6438
        • Vlassara H.
        • Brownlee M.
        • Manogue K.R.
        • Dinarello C.A.
        • Pasagian A.
        Cachetin/TNF and IL-1 induced by glucose-modified proteins: role in normal tissue remodeling.
        Science. 1988; 240: 1546-1548
        • Vlassara H.
        • Fuh H.
        • Donnelly T.
        • Cybulsky M.
        Advanced glycation endproducts promote adhesion molecule (VCAM-1, ICAM-1) expression and atheroma formation in normal rabbits.
        Mol. Med. 1995; 1: 447-456
        • Schmidt A.M.
        • Yan S.D.
        • Wautier J.L.
        • Stern D.
        Activation of receptor for advanced glycation endproducts; a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis.
        Circ. Res. 1999; 84: 489-497
        • Abordo E.A.
        • Thornalley P.J.
        Synthesis and secretion of macrophage colony stimulating factor by mature human monocytes and human monocytic THP-1 cells induced by human serum albumin derivatives modified with methylglyoxal and glucose-derived advanced glycation endproducts.
        Immunol. Lett. 1997; 58: 139-147
        • Chappey O.
        • Dosquet C.
        • Wautier M.P.
        • Wautier J.L.
        Advanced glycation end products, oxidant stress and vascular lesions.
        Eur. J. Clin. Invest. 1997; 27: 97-108
        • Brownlee M.
        • Vlassara H.
        • Kooney A.
        • Ulrich P.
        • Cerami A.
        Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking.
        Science. 1986; 232: 1629-1632
        • O'Brien J.
        Nutritional and toxicological aspects of the Maillard browning reaction in foods.
        Clin. Rev. Food Sci. Nutr. 1989; 28: 221-248
        • Finot P.A.
        • Magnenat E.
        Metabolic transit of early and advanced Maillard products.
        Prog. Food Nutr. Sci. 1981; 5: 193-207
        • Lee T.-C.
        • Kimaigar M.
        • Pintauro S.J.
        • Chichester C.O.
        Physiological and safety aspects of Maillard browning of foods.
        Prog. Food Nutr. Sci. 1981; 5: 243-256
        • Sgarbieri V.C.
        • Amaya J.
        • Tanaka M.
        • Chichester C.O.
        Nutritional consequences of the Maillard reaction. Amino acid availability from fructose-leucine and fructose-tryptophan in the rat.
        J. Nutr. 1973; 103: 657-663
        • Koschinsky T.
        • He C.J.
        • Mitsuhashi T.
        • Bucala R.
        • Liu C.
        • Buenting C.
        • et al.
        Orally absorbed reactive glycation products (glycotoxins): a potential risk factor in diabetic nephropathy.
        Proc. Natl. Acad. Sci. USA. 1997; 94: 6474-6479
        • 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
        • He C.
        • Li J.
        • Sabol J.
        • Hattori M.
        • Chang M.
        • Mitsuhashi T.
        • et al.
        AGE-restricted diet decreases incidence of diabetes and prolongs survival in NOD mice.
        Diabetes. 1999; 48 (abstract): A144
        • Hofmann S.M.
        • Dong H-J.
        • Zhu L.
        • Cai W.
        • Altomonte J.
        • Thung S.N.
        • et al.
        Improved insulin sensitivity is associated with restricted intake of dietary glycoxidation products in the db/db mouse.
        Diabetes. 2002; 51: 2082-2089
        • Zheng F.
        • He C.
        • Cai W.
        • Hattori M.
        • Steffes M.
        • Vlassara H.
        Prevention of diabetic nephropathy in mice by a diet low in glycoxidation products.
        Diabetes/Metab. Res. Revs. 2002; 18: 224-237
        • Lin R.-Y.
        • Reis E.D.
        • Dore A.T.
        • Lu M.
        • Ghodsi N.
        • Fallon J.T.
        • et al.
        Lowering of dietary advanced glycation endproducts (AGE) reduced neointimal formation after arterial injury in genetically hypercholesterolemic mice.
        Atherosclerosis. 2002; 163: 303-311
        • Plump A.S.
        • Smith J.D.
        • Hayek T.
        • Aalto-Setala K.
        • Walsh A.
        • Verstuyft J.G.
        • et al.
        Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells.
        Cell. 1992; 71: 343-353
        • Breslow J.L.
        Mouse models of atherosclerosis.
        Science. 1996; 272: 685-688
        • Mellinghoff A.C.
        • Reininger A.J.
        • Wuerth J.P.
        • Founds H.
        • Landgraf R.
        • Hepp K.D.
        Formation of plasma advanced glycosylation end products (AGEs) has no influence on plasma viscosity.
        Diabetes Med. 1997; 14: 832-836
        • Cai W.
        • Gao Q.-D.
        • Zhu L.
        • Peppa M.
        • He C.
        • Vlassara H.
        Oxidative stress-inducing carbonyl compounds from common foods: novel mediators of cellular dysfunction.
        Mol. Med. 2002; 8: 337-346
        • Reis E.D.
        • Roque M.
        • Dansky H.
        • Fallon J.T.
        • Badimon J.J.
        • Cordon-Cardo C.
        • et al.
        Sulindac inhibits neointimal formation after arterial injury in wild-type and apolipoprotein E-deficient mice.
        Proc. Natl. Acad. Sci. USA. 2000; 97: 12764-12769
        • Roque M.
        • Fallon J.T.
        • Badimon J.J.
        • Zhang W.X.
        • Taubman M.B.
        • Reis E.D.
        Mouse model of femoral artery denudation injury associated with the rapid accumulation of adhesion molecule on the luminal surface and recruitment of neutrophils.
        Arterioscler. Thromb. Vasc. Biol. 2000; 20: 335-342
        • Mitsuhashi T.
        • Vlassara H.
        • Founds H.W.
        • Li Y.M.
        Standardizing the immunological measurement of advanced glycation endproducts using normal human serum.
        J. Immunol. Methods. 1997; 207: 79-88
        • Nakamura Y.
        • Horii Y.
        • Nishino T.
        • Shiiki H.
        • Sakaguchi Y.
        • Kagoshima 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
        • Li Y.M.
        • Mitsuhashi T.
        • Wojciechowicz D.
        • Shimizu N.
        • Li J.
        • Stitt A.
        • et al.
        Molecular identity and cellular distribution of advanced glycation endproduct receptors: relationship of p60 to ost-48 and p90 to 80K-h membrane proteins.
        Proc. Natl. Acad. Sci. USA. 1996; 93: 11047-11052
        • Fu M.X.
        • Requena J.R.
        • Jenkins A.J.
        • Lyons T.J.
        • Baynes J.W.
        • Thorpe S.R.
        The advanced glycation end product, N epsilon-(carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation reactions.
        J. Biol. Chem. 1996; 27: 19982-19986
        • Reddy S.
        • Bichler J.
        • Wells-Knecht K.J.
        • Thorpe S.R.
        • Baynes J.W.
        N epsilon-(carboxymethyl)lysine is a dominant advanced glycation end product (AGE) antigen in tissue proteins.
        Biochemistry. 1995; 34: 10872-10878
        • Shamshi F.A.
        • Partal A.
        • Sady C.
        • Glomb M.A.
        • Nagaraj R.H.
        Immunological evidence for methylglyoxal-derived modifications in vivo.
        J. Biol. Chem. 1998; 273: 6928-6936
      2. Karmas E. Harris R.S. Nutritional evaluation of food processing. 3rd ed. Van Nostrand Reinhold, New York, NY1995
        • Mottram D.S.
        • Elmore J.S.
        The interaction of lipid-derived aldehydes with the Maillard reaction in meat systems.
        in: O'Brien J. The Maillard reaction in foods and medicine. The Royal Society of Chemistry, Cambridge, UK1998: 198-203
        • Ledl F.
        • Schleicher E.
        New aspects of the Maillard reaction in foods and in the human body.
        Angew. Chem. Int. Ed. Engl. 1990; 29: 565-594
        • Meng J.
        • Sakata N.
        • Takebayashi S.
        • et al.
        Glycoxidation in aortic collagen from STZ-induced diabetic rats and its relevance to vascular damage.
        Atherosclerosis. 1998; 136: 355-365
        • Miyata T.
        • Kurokawa K.
        • Van Ypersele D.
        • Strihou C.
        Advanced glycation and lipoxidation end products: role of reactive carbonyl compounds generated during carbohydrate and lipid metabolism.
        J. Am. Soc. Nephrol. 2000; 9: 1744-1752
        • Vlassara H.
        • Cai W.
        • Crandall J.
        • Goldberg T.
        • Oberstein R.
        • Dardaine V.
        • Peppa M.
        • Rayfield E.
        Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy.
        PNAS. 2002; 99: 15596-15601
        • Jager A.
        • van Hinsbergh V.W.
        • Kostense P.J.
        • Emeis J.J.
        • Nijpels G.
        • Dekker J.M.
        • et al.
        Arterioscler. Thromb. Vasc. Biol. 1999; 19: 3071-3078
        • Stitt A.W.
        • He C.
        • Friedman S.
        • Scher L.
        • Rossi P.
        • Ong L.
        • et al.
        Elevated AGE-modified apoB in sera of euglycemic, normolipidemic patients with atherosclerosis: relationship to tissue AGEs.
        Mol. Med. 1997; 3: 617-627
        • Park L.
        • Raman K.G.
        • Lee K.J.
        • Lu Y.
        • Ferran Jr., L.J.
        • Chow W.S.
        • et al.
        Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts.
        Nat. Med. 1998; 4: 1025-1031
      3. Nutrient Requirements of Laboratory Animals. 4th ed. ISBN 0309051226. Subcommittee on Laboratory Animal Nutrition, National Research Council, Washington, DC, USA, 1995.