Abstract
Aims/hypothesisReactive α-dicarbonyl compounds are major precursors of AGEs and may lead to glycation of circulating and/or cell-associated complement regulators. Glycation of complement regulatory proteins can influence their capacity to inhibit complement activation. We investigated, in a human cohort, whether greater dicarbonyl stress was associated with more complement activation.MethodsCirculating concentrations of dicarbonyl stress markers, i.e. α-dicarbonyls (methylglyoxal [MGO], glyoxal [GO] and 3-deoxyglucosone [3-DG]), and free AGEs (Nε-(carboxymethyl)lysine [CML], Nε-(carboxyethyl)lysine [CEL] and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine [MG-H1]), and protein-bound AGEs (CML, CEL, pentosidine), as well as the complement activation products C3a and soluble C5b-9 (sC5b-9), were measured in 530 participants (59.5 ± 7.0 years [mean ± SD], 61% men) of the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study. Multiple linear regression analyses were used to investigate the associations between dicarbonyl stress (standardised) and complement activation (standardised) with adjustment of potential confounders, including age, sex, lifestyle, use of medication and markers of obesity. In addition, the associations of two potentially functional polymorphisms (rs1049346, rs2736654) in the gene encoding glyoxalase 1 (GLO1), the rate-limiting detoxifying enzyme for MGO, with C3a and sC5b-9 (all standardized) were evaluated.ResultsAfter adjustment for potential confounders, plasma concentration of the dicarbonyl GO was inversely associated with sC5b-9 (β −0.12 [95% CI –0.21, −0.02]) and the protein-bound AGE CEL was inversely associated with C3a (−0.17 [−0.25, −0.08]). In contrast, the protein-bound AGE pentosidine was positively associated with sC5b-9 (0.15 [0.05, 0.24]). No associations were observed for other α-dicarbonyls and other free or protein-bound AGEs with C3a or sC5b-9. Individuals with the AG and AA genotype of rs1049346 had, on average, 0.32 and 0.40 SD lower plasma concentrations of sC5b-9 than those with the GG genotype, while concentrations of C3a did not differ significantly between rs1049346 genotypes. GLO1 rs2736654 was not associated with either C3a or sC5b-9.Conclusions/interpretationPlasma concentrations of dicarbonyl stress markers showed distinct associations with complement activation products: some of them were inversely associated with either C3a or sC5b-9, while protein-bound pentosidine was consistently and positively associated with sC5b-9. This suggests different biological relationships of individual dicarbonyl stress markers with complement activation.
Highlights
Chronic hyperglycaemia can induce dicarbonyl stress, which is characterised by increased presence of reactive αdicarbonyl compounds and AGEs [1, 2]
In this study we investigated to what extent dicarbonyl stress, as reflected by the presence of dicarbonyls and AGEs in the circulation, is related to complement activation, as represented by the plasma concentrations of two complement activation products, i.e. C3a and soluble (s)C5b-9
Plasma and serum aliquots were stored at −80°C until use. α-dicarbonyls, free AGEs (Nε-(carboxymethyl)lysine [CML], Nε-(carboxyethyl)lysine [CEL], Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine [MG-H1]), and protein-bound CML and CEL were measured in EDTA plasma by ultra HPLC-tandem MS (Waters, Milford, MA, USA)
Summary
Chronic hyperglycaemia can induce dicarbonyl stress, which is characterised by increased presence of reactive αdicarbonyl compounds and AGEs [1, 2]. Prolonged exposure of proteins to α-dicarbonyl compounds may change their normal function and/or their susceptibility to enzymatic degradation [3]. C3 convertases that are generated can cleave the central component of the complement cascade, C3, into C3b and the anaphylatoxin C3a (as reviewed in [9], see Fig. 1). Uncontrolled complement activation can damage host cells and/or hyperactivate inflammatory pathways [10]. The complement system is under strict control by circulating and cell-surface inhibitors (as reviewed in [9, 11])
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