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Nur E.,Slotervaart Hospital | Brandjes D.P.,Slotervaart Hospital | Schnog J.-J.B.,Slotervaart Hospital | Otten H.-M.,Slotervaart Hospital | Schalkwijk C.G.,Laboratory for Metabolism and Vascular Medicine
British Journal of Haematology | Year: 2010

Oxidative stress plays an important role in the pathophysiology of sickle cell disease (SCD). Plasma levels of advanced glycation end products (AGEs) are increased under oxidative conditions and are associated with disease severity in diabetes and inflammatory diseases. We investigated whether AGEs are increased in sickle cell patients and whether they are associated with SCD-related complications. Plasma levels of the AGEs pentosidine, Nε- (carboxymethyl)lysine (CML) and Nε-(carboxyethyl)lysine (CEL) were measured using single-column high performance liquid chromatography with fluorescence detection (pentosidine) and ultra performance liquid chromatography-tandem mass spectrometry (CML and CEL). Plasma levels of pentosidine and CML were increased in HbSS/HbSβ0-thalassaemia (n = 60) and HbSC/HbSβ+-thalassaemia (n = 42) patients during steady state as compared to healthy HbAA controls (n = 30) without increments during painful crisis. CEL levels were comparable between all groups. Pentosidine and CML levels correlated significantly to haemolytic rate during the clinically asymptomatic state while pentosidine was significantly related to the number of haemolysis-related organ complications. The increased plasma AGE levels in sickle cell patients and their association with haemolysis and haemolysis-related complications suggest AGEs might be implicated in the pathophysiology of the haemolytic phenotype of SCD. Measurement of AGEs might be useful in predicting organ complications in SCD. © 2010 Blackwell Publishing Ltd. Source


Hanssen N.M.J.,Maastricht University | Hanssen N.M.J.,Laboratory for Metabolism and Vascular Medicine | Brouwers O.,Maastricht University | Brouwers O.,Laboratory for Metabolism and Vascular Medicine | And 14 more authors.
Cardiovascular Research | Year: 2014

Aims Advanced glycation end-products (AGEs) and their precursors have been associated with the development of atherosclerosis. We recently discovered that glyoxalase 1 (GLO1), the major detoxifying enzyme for AGE precursors, is decreased in ruptured human plaques, and that levels of AGEs are higher in rupture-prone plaques. We here investigated whether overexpression of human GLO1 in ApoE-/- mice could reduce the development of atherosclerosis. Methods and results We crossed C57BL/6 ApoE-/- mice with C57BL/6 GLO1 overexpressing mice (huGLO1+/-) to generate ApoE-/- (n = 16) and ApoE-/- huGLO1+/- (n = 20) mice. To induce diabetes, we injected a subset with streptozotocin (STZ) to generate diabetic ApoE-/- (n = 8) and ApoE-/- huGLO1+/- (n = 13) mice. All mice were fed chow and sacrificed at 25 weeks of age. The GLO1 activity was three-fold increased in huGLO1+/- aorta, but aortic root lesion size and phenotype did not differ between mice with and without huGLO1+/- overexpression. We detected no differences in gene expression in aortic arches, in AGE levels and cytokines, in circulating cells, and endothelial function between ApoE-/- mice with and without huGLO1+/- overexpression. Although diabetic mice showed decreased GLO1 expression (P < 0.05) and increased lesion size (P < 0.05) in comparison with non-diabetic mice, GLO1 overexpression also did not affect the aortic root lesion size or inflammation in diabetic mice. Conclusion In ApoE-/- mice with or without diabetes, GLO1 overexpression did not lead to decreased atherosclerotic lesion size or systemic inflammation. Increasing GLO1 levels does not seem to be an effective strategy to reduce glycation in atherosclerotic lesions, likely due to increased AGE formation through GLO1-independent mechanisms. © 2014 Published on behalf of the European Society of Cardiology. Source


van Greevenbroek M.M.J.,Laboratory for Metabolism and Vascular Medicine | Arts I.C.W.,Maastricht University | van der Kallen C.J.H.,Laboratory for Metabolism and Vascular Medicine | Dagnelie P.C.,Maastricht University | And 5 more authors.
Journal of Nutrition | Year: 2014

Complement factor 3 (C3) has been identified as a novel risk factor for obesity-associated cardiometabolic diseases. Data in the literature suggest that C3 concentrations may be influenced by diet. Therefore, we investigated the associations of intake of total fat, specific fatty acids, and fat-soluble vitamin E (and individual tocopherols) and vitamin A (and its dietary precursors) with circulating C3. In a white cohort [Cohort on Diabetes and Atherosclerosis Maastricht (CODAM); n = 501; 59.4 +7.1 y; 61% men], associations of habitual nutrient intake (assessed by a food-frequency questionnaire) with circulating C3 were evaluated by using cross-sectionalmultiple linear regression analyses. Adjustments were first performed for age, sex, glucose metabolism status (i.e., impaired glucose metabolism or type 2 diabetes), and energy intake and subsequently for BMI,waist circumference, alcohol intake, smoking behavior, and season of blood collection. No associations with C3 were observed for total dietary fat intake or intake of specific fatty acids [saturated, monounsaturated, polyunsaturated, n-6 (ω-6), and n-3 (ω-3) fatty acids], vitamin E, or individual tocopherols. We observed an inverse association with intake of provitamin A carotenoids a-carotene (in μg/d; regression coefficient β= -0.075; 95% CI: -0.140, -0.010; P = 0.025) and β-carotene (in μg/d; β= -0.021; 95% CI: -0.044, 0.002; P = 0.068) with C3 (in mg/L). In contrast, and only in women, dietary retinol intake (in mg/d) was positively associated with C3 (β= 0.116; 95% CI: 0.014, 0.218; P = 0.026; n = 196). In conclusion, these data suggest that fasting concentrations of C3 may, in a complex manner, be modifiable by variation in dietary provitamin A carotenoids and/or retinol content of the usual diet but most likely not by variations in fat composition and vitamin E content. © 2014 American Society for Nutrition. Source


Hanssen N.M.J.,Maastricht University | Hanssen N.M.J.,Laboratory for Metabolism and Vascular Medicine | Wouters K.,Maastricht University | Wouters K.,Laboratory for Metabolism and Vascular Medicine | And 18 more authors.
European Heart Journal | Year: 2014

Aims Rupture-prone atherosclerotic plaques are characterized by inflammation and a large necrotic core. Inflammation is linked to high metabolic activity. Advanced glycation endproducts (AGEs) and their major precursor methylglyoxal are formed during high metabolic activity and can have detrimental effects on cellular function and may induce cell death. Therefore, we investigated whether plaque AGEs are increased in human carotid rupture-prone plaques and are associated with plaque inflammation and necrotic core formation. Methods and results The protein-bound major methylglyoxal-derived AGE 5-hydro-5-methylimidazolone (MG-H1) and NE-(carboxymethyl)lysine (CML) were measured in human carotid endarterectomy specimens (n = 75) with tandem mass spectrometry. MG-H1 and CML levels were associated with rupture-prone plaques, increased protein levels of the inflammatory mediators IL-8 and MCP-1 and with higher MMP-9 activity. Immunohistochemistry showed that AGEs accumulated predominantly in macrophages surrounding the necrotic core and co-localized with cleaved caspase-3. Intra-plaque comparison revealed that glyoxalase-1 (GLO-1), the major methylglyoxal-detoxifying enzyme, mRNA was decreased (-13%, P < 0.05) in ruptured compared with stable plaque segments. In line, in U937 monoctyes, we found reduced (GLO-1) activity (-38%, P < 0.05) and increased MGO (346%, P < 0.05) production after stimulation with the inflammatory mediator TNF. Direct incubation with methylglyoxal increased apoptosis up to two-fold. Conclusion This is the first study showing that AGEs are associated with human rupture-prone plaques. Furthermore, this study suggests a cascade linking inflammation, reduced GLO-1, methylglyoxal- and AGE-accumulation, and subsequent apoptosis. Thereby, AGEs may act as mediators of the progression of stable to rupture-prone plaques, opening a window towards novel treatments and biomarkers to treat cardiovascular diseases. © The Author 2013. Source

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