Abstract
N(epsilon)-(Carboxymethyl)lysine (CML), a major product of oxidative modification of glycated proteins, has been suggested to represent a general marker of oxidative stress and long-term damage to proteins in aging, atherosclerosis, and diabetes. To investigate the occurrence and distribution of CML in humans an antiserum specifically recognizing protein-bound CML was generated. The oxidative formation of CML from glycated proteins was reduced by lipoic acid, aminoguanidine, superoxide dismutase, catalase, and particularly vitamin E and desferrioxamine. Immunolocalization of CML in skin, lung, heart, kidney, intestine, intervertebral discs, and particularly in arteries provided evidence for an age-dependent increase in CML accumulation in distinct locations, and acceleration of this process in diabetes. Intense staining of the arterial wall and particularly the elastic membrane was found. High levels of CML modification were observed within atherosclerotic plaques and in foam cells. The preferential location of CML immunoreactivity in lesions may indicate the contribution of glycoxidation to the processes occurring in diabetes and aging. Additionally, we found increased CML content in serum proteins in diabetic patients. The strong dependence of CML formation on oxidative conditions together with the increased occurrence of CML in diabetic serum and tissue proteins suggest a role for CML as endogenous biomarker for oxidative damage.
Full Text
The Full Text of this article is available as a PDF (680.5 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Ahmed M. U., Thorpe S. R., Baynes J. W. Identification of N epsilon-carboxymethyllysine as a degradation product of fructoselysine in glycated protein. J Biol Chem. 1986 Apr 15;261(11):4889–4894. [PubMed] [Google Scholar]
- Baynes J. W. Role of oxidative stress in development of complications in diabetes. Diabetes. 1991 Apr;40(4):405–412. doi: 10.2337/diab.40.4.405. [DOI] [PubMed] [Google Scholar]
- Beisswenger P. J., Moore L. L., Brinck-Johnsen T., Curphey T. J. Increased collagen-linked pentosidine levels and advanced glycosylation end products in early diabetic nephropathy. J Clin Invest. 1993 Jul;92(1):212–217. doi: 10.1172/JCI116552. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brownlee M., Cerami A., Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med. 1988 May 19;318(20):1315–1321. doi: 10.1056/NEJM198805193182007. [DOI] [PubMed] [Google Scholar]
- Bucala R., Cerami A. Advanced glycosylation: chemistry, biology, and implications for diabetes and aging. Adv Pharmacol. 1992;23:1–34. doi: 10.1016/s1054-3589(08)60961-8. [DOI] [PubMed] [Google Scholar]
- Chang J. C., Ulrich P. C., Bucala R., Cerami A. Detection of an advanced glycosylation product bound to protein in situ. J Biol Chem. 1985 Jul 5;260(13):7970–7974. [PubMed] [Google Scholar]
- Dolhofer-Bliesener R., Lechner B., Gerbitz K. D. Impaired immunoglobulin G Fc fragment function in diabetics is caused by a mechanism different from glycation. Eur J Clin Chem Clin Biochem. 1994 May;32(5):329–336. doi: 10.1515/cclm.1994.32.5.329. [DOI] [PubMed] [Google Scholar]
- Dominiczak M. H., Bell J., Cox N. H., McCruden D. C., Jones S. K., Finlay A. Y., Percy-Robb I. W., Frier B. M. Increased collagen-linked fluorescence in skin of young patients with type I diabetes mellitus. Diabetes Care. 1990 May;13(5):468–472. doi: 10.2337/diacare.13.5.468. [DOI] [PubMed] [Google Scholar]
- Dunn J. A., McCance D. R., Thorpe S. R., Lyons T. J., Baynes J. W. Age-dependent accumulation of N epsilon-(carboxymethyl)lysine and N epsilon-(carboxymethyl)hydroxylysine in human skin collagen. Biochemistry. 1991 Feb 5;30(5):1205–1210. doi: 10.1021/bi00219a007. [DOI] [PubMed] [Google Scholar]
- Dunn J. A., Patrick J. S., Thorpe S. R., Baynes J. W. Oxidation of glycated proteins: age-dependent accumulation of N epsilon-(carboxymethyl)lysine in lens proteins. Biochemistry. 1989 Nov 28;28(24):9464–9468. doi: 10.1021/bi00450a033. [DOI] [PubMed] [Google Scholar]
- Dyer D. G., Dunn J. A., Thorpe S. R., Bailie K. E., Lyons T. J., McCance D. R., Baynes J. W. Accumulation of Maillard reaction products in skin collagen in diabetes and aging. J Clin Invest. 1993 Jun;91(6):2463–2469. doi: 10.1172/JCI116481. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fu M. X., Knecht K. J., Thorpe S. R., Baynes J. W. Role of oxygen in cross-linking and chemical modification of collagen by glucose. Diabetes. 1992 Oct;41 (Suppl 2):42–48. doi: 10.2337/diab.41.2.s42. [DOI] [PubMed] [Google Scholar]
- Fu M. X., Requena J. R., Jenkins A. J., Lyons T. J., Baynes J. W., Thorpe S. R. The advanced glycation end product, Nepsilon-(carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation reactions. J Biol Chem. 1996 Apr 26;271(17):9982–9986. doi: 10.1074/jbc.271.17.9982. [DOI] [PubMed] [Google Scholar]
- Fu M. X., Wells-Knecht K. J., Blackledge J. A., Lyons T. J., Thorpe S. R., Baynes J. W. Glycation, glycoxidation, and cross-linking of collagen by glucose. Kinetics, mechanisms, and inhibition of late stages of the Maillard reaction. Diabetes. 1994 May;43(5):676–683. doi: 10.2337/diab.43.5.676. [DOI] [PubMed] [Google Scholar]
- Horiuchi S., Araki N., Morino Y. Immunochemical approach to characterize advanced glycation end products of the Maillard reaction. Evidence for the presence of a common structure. J Biol Chem. 1991 Apr 25;266(12):7329–7332. [PubMed] [Google Scholar]
- Ikeda K., Higashi T., Sano H., Jinnouchi Y., Yoshida M., Araki T., Ueda S., Horiuchi S. N (epsilon)-(carboxymethyl)lysine protein adduct is a major immunological epitope in proteins modified with advanced glycation end products of the Maillard reaction. Biochemistry. 1996 Jun 18;35(24):8075–8083. doi: 10.1021/bi9530550. [DOI] [PubMed] [Google Scholar]
- Kennedy L., Baynes J. W. Non-enzymatic glycosylation and the chronic complications of diabetes: an overview. Diabetologia. 1984 Feb;26(2):93–98. doi: 10.1007/BF00281113. [DOI] [PubMed] [Google Scholar]
- Knecht K. J., Dunn J. A., McFarland K. F., McCance D. R., Lyons T. J., Thorpe S. R., Baynes J. W. Effect of diabetes and aging on carboxymethyllysine levels in human urine. Diabetes. 1991 Feb;40(2):190–196. doi: 10.2337/diab.40.2.190. [DOI] [PubMed] [Google Scholar]
- Kume S., Takeya M., Mori T., Araki N., Suzuki H., Horiuchi S., Kodama T., Miyauchi Y., Takahashi K. Immunohistochemical and ultrastructural detection of advanced glycation end products in atherosclerotic lesions of human aorta with a novel specific monoclonal antibody. Am J Pathol. 1995 Sep;147(3):654–667. [PMC free article] [PubMed] [Google Scholar]
- Lyons T. J., Kennedy L. Non-enzymatic glycosylation of skin collagen in patients with type 1 (insulin-dependent) diabetes mellitus and limited joint mobility. Diabetologia. 1985 Jan;28(1):2–5. doi: 10.1007/BF00276991. [DOI] [PubMed] [Google Scholar]
- Makita Z., Vlassara H., Cerami A., Bucala R. Immunochemical detection of advanced glycosylation end products in vivo. J Biol Chem. 1992 Mar 15;267(8):5133–5138. [PubMed] [Google Scholar]
- McCance D. R., Dyer D. G., Dunn J. A., Bailie K. E., Thorpe S. R., Baynes J. W., Lyons T. J. Maillard reaction products and their relation to complications in insulin-dependent diabetes mellitus. J Clin Invest. 1993 Jun;91(6):2470–2478. doi: 10.1172/JCI116482. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mitsuhashi T., Nakayama H., Itoh T., Kuwajima S., Aoki S., Atsumi T., Koike T. Immunochemical detection of advanced glycation end products in renal cortex from STZ-induced diabetic rat. Diabetes. 1993 Jun;42(6):826–832. doi: 10.2337/diab.42.6.826. [DOI] [PubMed] [Google Scholar]
- Miyata S., Monnier V. Immunohistochemical detection of advanced glycosylation end products in diabetic tissues using monoclonal antibody to pyrraline. J Clin Invest. 1992 Apr;89(4):1102–1112. doi: 10.1172/JCI115690. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Monnier V. M., Kohn R. R., Cerami A. Accelerated age-related browning of human collagen in diabetes mellitus. Proc Natl Acad Sci U S A. 1984 Jan;81(2):583–587. doi: 10.1073/pnas.81.2.583. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Monnier V. M., Vishwanath V., Frank K. E., Elmets C. A., Dauchot P., Kohn R. R. Relation between complications of type I diabetes mellitus and collagen-linked fluorescence. N Engl J Med. 1986 Feb 13;314(7):403–408. doi: 10.1056/NEJM198602133140702. [DOI] [PubMed] [Google Scholar]
- Nakamura Y., Horii Y., Nishino T., Shiiki H., Sakaguchi Y., Kagoshima T., Dohi K., Makita Z., Vlassara H., Bucala R. Immunohistochemical localization of advanced glycosylation end products in coronary atheroma and cardiac tissue in diabetes mellitus. Am J Pathol. 1993 Dec;143(6):1649–1656. [PMC free article] [PubMed] [Google Scholar]
- Nerlich A., Schleicher E. Immunohistochemical localization of extracellular matrix components in human diabetic glomerular lesions. Am J Pathol. 1991 Oct;139(4):889–899. [PMC free article] [PubMed] [Google Scholar]
- Njoroge F. G., Sayre L. M., Monnier V. M. Detection of D-glucose-derived pyrrole compounds during Maillard reaction under physiological conditions. Carbohydr Res. 1987 Sep 15;167:211–220. doi: 10.1016/0008-6215(87)80280-x. [DOI] [PubMed] [Google Scholar]
- Palinski W., Koschinsky T., Butler S. W., Miller E., Vlassara H., Cerami A., Witztum J. L. Immunological evidence for the presence of advanced glycosylation end products in atherosclerotic lesions of euglycemic rabbits. Arterioscler Thromb Vasc Biol. 1995 May;15(5):571–582. doi: 10.1161/01.atv.15.5.571. [DOI] [PubMed] [Google Scholar]
- Pongor S., Ulrich P. C., Bencsath F. A., Cerami A. Aging of proteins: isolation and identification of a fluorescent chromophore from the reaction of polypeptides with glucose. Proc Natl Acad Sci U S A. 1984 May;81(9):2684–2688. doi: 10.1073/pnas.81.9.2684. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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 Aug 29;34(34):10872–10878. doi: 10.1021/bi00034a021. [DOI] [PubMed] [Google Scholar]
- Schleicher E., Wieland O. H. Kinetic analysis of glycation as a tool for assessing the half-life of proteins. Biochim Biophys Acta. 1986 Oct 29;884(1):199–205. doi: 10.1016/0304-4165(86)90244-8. [DOI] [PubMed] [Google Scholar]
- Schleicher E., Wieland O. H. Specific quantitation by HPLC of protein (lysine) bound glucose in human serum albumin and other glycosylated proteins. J Clin Chem Clin Biochem. 1981 Feb;19(2):81–87. doi: 10.1515/cclm.1981.19.2.81. [DOI] [PubMed] [Google Scholar]
- Sell D. R., Carlson E. C., Monnier V. M. Differential effects of type 2 (non-insulin-dependent) diabetes mellitus on pentosidine formation in skin and glomerular basement membrane. Diabetologia. 1993 Oct;36(10):936–941. doi: 10.1007/BF02374476. [DOI] [PubMed] [Google Scholar]
- Sell D. R., Lapolla A., Odetti P., Fogarty J., Monnier V. M. Pentosidine formation in skin correlates with severity of complications in individuals with long-standing IDDM. Diabetes. 1992 Oct;41(10):1286–1292. doi: 10.2337/diab.41.10.1286. [DOI] [PubMed] [Google Scholar]
- Sell D. R., Monnier V. M. Structure elucidation of a senescence cross-link from human extracellular matrix. Implication of pentoses in the aging process. J Biol Chem. 1989 Dec 25;264(36):21597–21602. [PubMed] [Google Scholar]
- Smith P. R., Thornalley P. J. Mechanism of the degradation of non-enzymatically glycated proteins under physiological conditions. Studies with the model fructosamine, N epsilon-(1-deoxy-D-fructos-1-yl)hippuryl-lysine. Eur J Biochem. 1992 Dec 15;210(3):729–739. doi: 10.1111/j.1432-1033.1992.tb17474.x. [DOI] [PubMed] [Google Scholar]
- Vishwanath V., Frank K. E., Elmets C. A., Dauchot P. J., Monnier V. M. Glycation of skin collagen in type I diabetes mellitus. Correlation with long-term complications. Diabetes. 1986 Aug;35(8):916–921. doi: 10.2337/diab.35.8.916. [DOI] [PubMed] [Google Scholar]
- Vlassara H., Brownlee M., Cerami A. High-affinity-receptor-mediated uptake and degradation of glucose-modified proteins: a potential mechanism for the removal of senescent macromolecules. Proc Natl Acad Sci U S A. 1985 Sep;82(17):5588–5592. doi: 10.1073/pnas.82.17.5588. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vogt B. W., Schleicher E. D., Wieland O. H. epsilon-Amino-lysine-bound glucose in human tissues obtained at autopsy. Increase in diabetes mellitus. Diabetes. 1982 Dec;31(12):1123–1127. doi: 10.2337/diacare.31.12.1123. [DOI] [PubMed] [Google Scholar]
- Wells-Knecht M. C., Thorpe S. R., Baynes J. W. Pathways of formation of glycoxidation products during glycation of collagen. Biochemistry. 1995 Nov 21;34(46):15134–15141. doi: 10.1021/bi00046a020. [DOI] [PubMed] [Google Scholar]