Oxidative damage to extracellular matrix and its role in human pathologies

Parsons

Houée-Levin⊥

et al. 2013

Hypochlorous acid and its acid-base counterpart, hypochlorite ions, produced in inflammatory conditions, may produce chloramides of glycosaminoglycans, the latter being significant components of the extracellular matrix (ECM). This may occur through the binding of myeloperoxidase directly to the glycosaminoglycans.The N-Cl group in the chloramides is a potential selective target for both reducing and oxidising radicals, leading possibly to more efficient and damaging fragmentation of these biopolymers relative to the parent glycosaminoglycans. In this study,the fast reaction techniques of pulse radiolysis and nanosecond laser flash photolysis have been used to generate both oxidizing and reducing radicals to react with the chloramides of hyaluronan (HACl) and heparin (HepCl).The strong reducing formate radicals and hydrated electrons were found to react rapidly with both HACl and HepCl with rate constants of (1-1.7) x 10 8 M -1 s -1 and (0.7-1.2) x 10 8 M -1 s -1 for formate radicals and 2.2 x 10 9 M -1 s and 7.2 x 10 8 M -1 s -1 for hydrated electrons, respectively. The spectral characteristics of the products of these reactions were identical and were consistent with initial attack at the N-Cl groups, followed by elimination of chloride ions to produce nitrogencentred radicals, which re-arrange subsequently and rapidly to produce C-2 radicals on the glucosamine moiety supporting an earlier EPR study by Rees et 3 This is the first study therefore to conclusively demonstrate that reducing radicals react rapidly with glycosaminoglycan chloramides in a site-specific attack at the N-Cl groups, probably to produce a 100 % efficient biopolymer fragmentation process. Although less reactive, carbonate radicals, which may be produced in vivo via reactions of peroxynitrite with serum levels of carbon dioxide ,also appear to react in a highly site-specific manner at the N-Cl group. It is not yet known if such site-specific attacks by this important in vivo species lead to a more efficient fragmentation of the biopolymers than would be expected for attack by the stronger oxidising species, the hydroxyl radical. It is clear however that the N-Cl group formed in inflammatory conditions in the extracellular matrix does present a more likely target for both reactive oxygen species and for reducing species than the N-H groups in the parent glycosaminoglycans. Graphical abstract4

Section: Introductionmentioning

confidence: 99%

One-electron oxidation and reduction of glycosaminoglycan chloramides: A kinetic study

Parsons

Houée-Levin⊥

et al. 2013

“…Oxidative damage to hyaluronan by reactive oxidative species, and in particular free radicals, has received much attention, largely through the ease of monitoring its fragmentation using viscometric techniques, which is reviewed in [13]. The potential mechanism of oxidative damage to the ECM and its role in human pathologies has also been discussed in a recent review [14].…”

Section: Introductionmentioning

confidence: 99%

Reaction of superoxide radicals with glycosaminoglycan chloramides: a kinetic study

Parsons

Heyes

et al. 2013

Hypochlorous acid and its acid-base counterpart, hypochlorite ions, produced in inflammatory conditions, may produce chloramides of glycosaminoglycans, perhaps through the binding of myeloperoxidase directly to the glycosaminoglycans. The N-Cl group in the chloramides is a potential target for reducing species such as Cu(I) and superoxide radicals. Laser flash photolysis has been used here to obtain, for the first time, the rate constants for the direct reaction of superoxide radicals with the chloramides of hyaluronan and heparin. The rate constants were in the range 2.2 -2.7 x 10 3 M -1 s -1 . The rate constant for the reaction with the amino acid, taurine, was found to be much lower at 3.5 -4.0 x 10 2 M -1 s -1 . This demonstration that superoxide anion radicals react directly with hyaluronan and heparin chloramides may support the mechanism first proposed by Rees et al, Biochem. J. 381: 175-184; for an efficient fragmentation of these glycosaminoglycans in the extracellular matrix under inflammatory conditions. 3

“…hypochlorite + HA => HACl + products (13) hypochlorite + HACl => products (14) Figure 7 a) The decay of absorbance at 292nm observed in a solution of 5 mM hypochlorite containing 10 mM hyaluronan at pH 6.5. Also shown is the simulated fit for k (hypochlorite + HA) = 9.5 x 10 -3 M -1 s -1 and k (hypochlorite + HACl) = 2.8 x 10 -2 M -1 s -1 b) the effect of pH on k (hypochlorite + HACl ), see text.…”

Section: Kinetic Studies In 5mm Hypochlorite Solutionsmentioning

confidence: 99%

“…These include arthritis, kidney disease, cardiovascular disease, lung disease, periodontal disease and chronic inflammation. The potential mechanisms of oxidative damage in these diseases has been reviewed recently [13].…”

Section: Introductionmentioning

confidence: 99%

Chlorination and oxidation of heparin and hyaluronan by hypochlorous acid and hypochlorite anions: effect of sulfate groups on reaction pathways and kinetics

Akeel

Martin

et al. 2013

Hypochlorous acid (HOCl), produced in inflammatory conditions by the enzyme myeloperoxidase, and its anion, perchlorite ( OCl -) exist in vivo at almost equal concentrations. Their reactions with hyluronan and heparin (as a model for sulphated glycosaminoglycans in the extracellular matrix), have been studied as a function of pH. The major product in these reactions is the chloramide derivative of the glycosaminoglycans. Spectral, chloramide yield and kinetic measurements show sharply contrasting behaviour of heparin and hyaluronan and the data allow the calculation of second-order rate constants for the reactions of both HOCl and OCl -for all reaction pathways leading to the formation of chloramides and also oxidation products . By comparison with hyaluronan, it can be demonstrated that both N-sulphate and O-sulphate groups in heparin influence the proportions of these pathways in this glycosaminoglycan. Evidence is also given for further oxidation pathways involving a reaction of HOCl with the chloramide product of hyaluronan but not with heparin. The significance of these results for mechanisms of inflammation, particularly for fragmentation of extracellular matrix glycosaminoglycans is discussed.