Department of Internal Medicine, Maastricht University Medical Centre, Universiteitssingel 50, PO Box 616, 6200 MD, Maastricht, the Netherlands.
CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.
Diabetologia. 2020 May;63(5):1032-1042. doi: 10.1007/s00125-020-05098-4. Epub 2020 Jan 28.
AIMS/HYPOTHESIS: Reactive 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.
Circulating concentrations of dicarbonyl stress markers, i.e. α-dicarbonyls (methylglyoxal [MGO], glyoxal [GO] and 3-deoxyglucosone [3-DG]), and free AGEs (N-(carboxymethyl)lysine [CML], N-(carboxyethyl)lysine [CEL] and N-(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.
After 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/INTERPRETATION: Plasma 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.
目的/假设：反应性α-二羰基化合物是 AGEs 的主要前体，可能导致循环和/或细胞相关补体调节剂的糖化。补体调节蛋白的糖化会影响其抑制补体激活的能力。我们在人类队列中研究了更大的二羰基应激是否与更多的补体激活有关。
在 CODAM 研究中，我们测量了 530 名参与者（59.5±7.0 岁[均值±标准差]，61%为男性）的循环二羰基应激标志物（即α-二羰基化合物（甲基乙二醛[MGO]、乙二醛[GO]和 3-脱氧葡萄糖酮[3-DG]）、游离 AGEs（N-（羧甲基）赖氨酸[CML]、N-（羧乙基）赖氨酸[CEL]和 N-（5-羟基-5-甲基-4-咪唑啉-2-基）-鸟氨酸[MG-H1]）以及蛋白质结合的 AGEs（CML、CEL、戊糖），以及补体激活产物 C3a 和可溶性 C5b-9（sC5b-9）。我们使用多元线性回归分析来研究二羰基应激（标准化）和补体激活（标准化）之间的关联，包括年龄、性别、生活方式、用药情况和肥胖标志物。此外，我们还评估了编码 MGO 限速解毒酶-甘油醛酶 1（GLO1）的基因中两个潜在功能多态性（rs1049346、rs2736654）与 C3a 和 sC5b-9（均标准化）之间的关联。
在调整潜在混杂因素后，血浆 GO 二羰基浓度与 sC5b-9 呈负相关（β-0.12[95%CI-0.21，-0.02]），蛋白质结合的 AGE CEL 与 C3a 呈负相关（β-0.17[-0.25，-0.08]）。相反，蛋白质结合的 AGE 戊糖与 sC5b-9 呈正相关（0.15[0.05，0.24]）。其他α-二羰基化合物和其他游离或蛋白质结合的 AGEs 与 C3a 或 sC5b-9 均无关联。rs1049346 的 AG 和 AA 基因型个体的 sC5b-9 血浆浓度平均比 GG 基因型个体低 0.32 和 0.40 个标准差，而 C3a 浓度在 rs1049346 基因型之间无显著差异。GLO1 rs2736654 与 C3a 或 sC5b-9 均无关联。
结论/解释：血浆中二羰基应激标志物浓度与补体激活产物呈不同的关联：其中一些与 C3a 或 sC5b-9 呈负相关，而蛋白质结合的戊糖则与 sC5b-9 呈一致的正相关。这表明不同的二羰基应激标志物与补体激活之间存在不同的生物学关系。
