The role of nonenzymatic glycosylation, transition metals, and free radicals in the formation of collagen aggregates

Chace, Kenneth V.; Carubelli, R.; Nordquist, Robert E.

doi:10.1016/0003-9861(91)90223-6

Cited by 83 publications

(39 citation statements)

References 45 publications

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“…To further clarify the role of the sugar versus that of H 2 O 2 , we incubated tendons for 24 h only with 10 mM H 2 O 2 with or without 10 M Cu II and compared the results with similar tendons incubated with 100 mM ribose in aerated phosphate buffer. Whereas immediate TBT increase was noticed with ribose, no change was observed in Cu 2ϩ /H 2 O 2 incubated specimens (not shown), thereby proving the necessity of involving a sugar in the early phase of collagen cross-linking as observed earlier by Chace et al (14).…”

Section: Discussionsupporting

confidence: 76%

See 1 more Smart Citation

Involvement of Hydrogen Peroxide in Collagen Cross-linking by High Glucose in Vitro and in Vivo

Elgawish

Glomb

Friedlander

et al. 1996

Journal of Biological Chemistry

183

101

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The Maillard reaction has been implicated in crosslinking and fluorescence formation of collagen exposed to high glucose in vitro. However, several pharmacologic agents, whose action seems unrelated to pathways of nonenzymatic glycation, have been demonstrated to prevent cross-linking in diabetes. To clarify this discrepancy, kinetic changes in glycation, glycoxidation (carboxymethyllysine, CML), and cross-linking (measured as tendon breaking time, TBT) were evaluated in rat tail tendons incubated in 5 and 30 mM glucose in vitro and in tendons implanted in vivo into diabetic rat peritoneal cavity. In vitro, rates were found to be both O 2 -and glucose-dependent. Tendon preglycation and presence of added 2 mM glycosylamine and Amadori compounds (Amadori product of glucose and propylamine) catalyzed these changes in a primarily O 2 -dependent manner. In the presence of Amadori compounds, kinetic changes were dramatically increased and were preventable by addition of catalase to the medium. Tendons implanted into diabetic rat peritoneum became more rapidly glycoxidized and cross-linked when implanted at day 30 from diabetes onset (high tissue glycation) compared to day 3 (low tissue glycation) in spite of similar glycation kinetics, suggesting a mechanistic dissociation between glycation, glycoxidation, and crosslinking in diabetes. Indeed, intraperitoneal injection of catalase and other antioxidants dramatically suppressed cross-linking, fluorescence formation, and, to some extent, glycoxidation, without affecting glycation. This study confirms the role of oxidative stress in protein cross-linking by the Maillard reaction in vitro and provides the first evidence for a role of H 2 O 2 in crosslinking in diabetes. Whereas Amadori products are a potent source of H 2 O 2 formation in vitro, their precise contribution to H 2 O 2 generation and the actual role of Maillard reaction products in collagen cross-linking in diabetes requires further investigation.Considerable efforts have been devoted in recent years toward understanding of the pathogenetic mechanisms leading to collagen insolubilization in diabetes and aging (1-3). The rationale for this research lies in the hope that understanding the biochemical basis of stochastic mechanisms of damage to collagen will help elucidate their role in diabetic complications and aging. One key proposition is that protein cross-links are generated in the advanced Maillard reaction (4, 5). According to the original concept proposed by Hodge (6), the central molecule responsible for the advanced Maillard reaction is the Amadori product which, upon dehydration and rearrangement, forms highly reactive deoxyosones Ϫ potent precursors of protein cross-links. This concept was challenged by Namiki (7) who found that sugar fragmentation can also occur at the stage of the glycosylamine, or Schiff base, i.e. prior to the Amadori rearrangement. Glyoxal is then formed which can serve as a protein cross-link (8 -10). More recently, Wolff et al. (11) obtained evidence from in vitro experimenta...

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Section: Discussionsupporting

confidence: 76%

“…These investigators showed that removal of oxygen and the presence of metal chelators or free radical scavengers could uncouple collagen cross-linking and glycoxidation from collagen glycation (13). Similar experiments by Chace (14) showed that collagen insolubilization in the presence of glucose was dependent on the formation of reactive oxygen species.…”

mentioning

confidence: 83%

Involvement of Hydrogen Peroxide in Collagen Cross-linking by High Glucose in Vitro and in Vivo

Elgawish

Glomb

Friedlander

et al. 1996

Journal of Biological Chemistry

183

101

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“…Cross-linking of collagen in itro by exposure to glucose is virtually blocked under N # and in the presence of chelators, confirming the importance of oxidative events [254]. We have shown that proteins exposed to autoxidizing glucose contain protein-bound oxidizing and reducing species, later characterized as hydroperoxides and dopa [27,28,255].…”

Section: Productsupporting

confidence: 61%

Biochemistry and pathology of radical-mediated protein oxidation

Dean

Stocker

et al. 1997

Biochemical Journal

1,550

982

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Radical-mediated damage to proteins may be initiated by electron leakage, metal-ion-dependent reactions and autoxidation of lipids and sugars. The consequent protein oxidation is O2-dependent, and involves several propagating radicals, notably alkoxyl radicals. Its products include several categories of reactive species, and a range of stable products whose chemistry is currently being elucidated. Among the reactive products, protein hydroperoxides can generate further radical fluxes on reaction with transition-metal ions; protein-bound reductants (notably dopa) can reduce transition-metal ions and thereby facilitate their reaction with hydroperoxides; and aldehydes may participate in Schiff-base formation and other reactions. Cells can detoxify some of the reactive species, e.g. by reducing protein hydroperoxides to unreactive hydroxides. Oxidized proteins are often functionally inactive and their unfolding is associated with enhanced susceptibility to proteinases. Thus cells can generally remove oxidized proteins by proteolysis. However, certain oxidized proteins are poorly handled by cells, and together with possible alterations in the rate of production of oxidized proteins, this may contribute to the observed accumulation and damaging actions of oxidized proteins during aging and in pathologies such as diabetes, atherosclerosis and neurodegenerative diseases. Protein oxidation may also sometimes play controlling roles in cellular remodelling and cell growth. Proteins are also key targets in defensive cytolysis and in inflammatory self-damage. The possibility of selective protection against protein oxidation (antioxidation) is raised.

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“…The AGE formation in tissue proteins is enhanced by transition metal ions, oxidative stress, phosphate, and neighboring positively charged amino acids (Chace et al ., 1991; Breyer et al ., 2012). Whether any of these factors contributed to the higher level of capsule AGEs in cataractous lenses is not known and needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

AGEs in human lens capsule promote the TGFβ2‐mediated EMT of lens epithelial cells: implications for age‐associated fibrosis

et al. 2016

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SummaryProteins in basement membrane (BM) are long‐lived and accumulate chemical modifications during aging; advanced glycation endproduct (AGE) formation is one such modification. The human lens capsule is a BM secreted by lens epithelial cells. In this study, we have investigated the effect of aging and cataracts on the AGE levels in the human lens capsule and determined their role in the epithelial‐to‐mesenchymal transition (EMT) of lens epithelial cells. EMT occurs during posterior capsule opacification (PCO), also known as secondary cataract formation. We found age‐dependent increases in several AGEs and significantly higher levels in cataractous lens capsules than in normal lens capsules measured by LC‐MS/MS. The TGFβ2‐mediated upregulation of the mRNA levels (by qPCR) of EMT‐associated proteins was significantly enhanced in cells cultured on AGE‐modified BM and human lens capsule compared with those on unmodified proteins. Such responses were also observed for TGFβ1. In the human capsular bag model of PCO, the AGE content of the capsule proteins was correlated with the synthesis of TGFβ2‐mediated α‐smooth muscle actin (αSMA). Taken together, our data imply that AGEs in the lens capsule promote the TGFβ2‐mediated fibrosis of lens epithelial cells during PCO and suggest that AGEs in BMs could have a broader role in aging and diabetes‐associated fibrosis.

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The role of nonenzymatic glycosylation, transition metals, and free radicals in the formation of collagen aggregates

Cited by 83 publications

References 45 publications

Involvement of Hydrogen Peroxide in Collagen Cross-linking by High Glucose in Vitro and in Vivo

Involvement of Hydrogen Peroxide in Collagen Cross-linking by High Glucose in Vitro and in Vivo

Biochemistry and pathology of radical-mediated protein oxidation

AGEs in human lens capsule promote the TGFβ2‐mediated EMT of lens epithelial cells: implications for age‐associated fibrosis

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