Coen D.A. Stehouwer

Effect of methylglyoxal on the physico-chemical and biological properties of low-density lipoprotein

In patients with diabetes, non-enzymatic glycation of low-density lipoprotein (LDL) has been suggested to be involved in the development of atherosclerosis. alpha-Dicarbonyl compounds were identified as intermediates in the non-enzymatic glycation and increased levels were reported in patients with diabetes. We studied the effect of the alpha-dicarbonyl compound methylglyoxal (MG) on the physicochemical and biological properties of LDL. MG dose-dependently modifies LDL, as indicated by the formation of fluorescent products and the increase of a net negative charge. MG (10 mmol/l) induced major modifications of arginine residues (up to 85%) and minor lysine modifications (less than 6%). MG-LDL preparations generated small amounts of superoxide anion radicals as measured by the reduction of cytochrome c, but this was not accompanied by peroxidation of the polyunsaturated fatty acids of MG-LDL. MG-LDL showed diminished recognition and uptake by the human LDL receptor in cultured cells and a markedly increased plasma clearance rate in vivo in rats. The reduced association and degradation of 125I-oxidised LDL by murine macrophages indicates recognition of MG-LDL by a scavenger receptor. Surprisingly, MG-LDL caused significantly less cholesteryl ester synthesis in murine macrophages, as compared to native LDL and oxidised or acetylated LDL. Highly modified MG-LDL did not induce activation of human endothelial cells, as measured by the expression of monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1.

Serum 25-hydroxyvitamin D and parathyroid hormone in relation to plasma B-type natriuretic peptide: the Hoorn Study

Objective A disturbed vitamin D–parathyroid hormone (PTH)–calcium axis may play a role in the pathogenesis of heart failure. Therefore, we investigated whether lower 25-hydroxyvitamin D (25(OH)D) and higher PTH are cross sectionally and after 8 years of follow-up associated with higher B-type natriuretic peptide (BNP) levels in older men and women. Design and methods We measured baseline 25(OH)D, PTH, and BNP in 502 subjects in 2000–2001 in the Hoorn Study, a population-based cohort. Follow-up BNP was available in 2007–2009 in 278 subjects. Subjects were categorized according to season- and sex-specific quartiles of 25(OH)D and PTH at baseline. We studied the association of 25(OH)D and PTH quartiles with BNP using linear regression analyses adjusting for confounders. Analyses were stratified by kidney function estimated glomerular filtration rate (eGFR; ≤60u200aml/min per 1.73u200am2) because of significant interaction. Results At baseline, subjects had a mean age of 69.9±6.6 years, mean 25(OH)D level was 52.2±19.5u200anmol/l and mean PTH 6.1±2.4u200apmol/l. Cross sectionally, 25(OH)D was associated with BNP in subjects with impaired kidney function (eGFR ≤60u200aml/min) only. The association attenuated after adjustment for PTH. PTH was cross sectionally associated with BNP, also in subjects with impaired kidney function only: regression coefficient of highest quartile 9.9u200apmol/l (95% confidence interval 2.5, 17.4) with a significant trend across quartiles. Neither 25(OH)D nor PTH was associated with BNP in longitudinal analyses. Conclusion This study showed overall no strong association between 25(OH)D and BNP. However, PTH was associated with BNP in subjects with impaired kidney function and may point to a potential role in myocardial function.

Modification of Low-Density Lipoprotein by Methylglyoxal Alters its Physico-Chemical and Biological Properties

Nonenzymatic glycosylation of low-density lipoprotein (LDL) has been suggested to be involved in the development of atherosclerosis in patients with diabetes. Since α-dicarbonyl compounds were identified as intermediates in nonenzymatic glycosylation, we investigated the effect of the physiological α-dicarbonyl compound methylglyoxal (MG) on the physico-chemical and biological properties of LDL. MG modifies LDL in a timeand concentration-dependent manner as indicated by the production of fluorescent products and the increase in net-negative charge. Despite the production of superoxide anion radicals, LDL modification by MG is not accompanied by peroxidation of the polyunsaturated fatty acids. MG-LDL showed impaired recognition by the LDL receptor, but increased binding to scavenger receptors. However, MG-LDL did not enhance cholesteryl ester synthesis in murine macrophages.

PS1 - 10. Obesity induces CD11c + macrophages in murine adipose tissue which are distinctive from, but resemble, dendritic cells

During obesity, inflammatory ‘M1’ macrophages infiltrate adipose tissue (AT). These ‘M1’ AT macrophages (ATMs) express the dendritic cell marker CD11c. Dendritic cells are immune regulators that promote insulin resistance. However, it is unclear whether and how CD11c+ ATMs differ from dendritic cells and if they are activated by obesity.

PS8 - 36. Higher levels of complement C3a (activated C3) are cross-sectionally associated with higher carotid media thickness and lower ankle-arm blood pressure index: the CODAM Study

The complement system has been proposed to play a role in the development of cardiovascular disease (CVD) and diabetes. The aim of this study was to investigate the association of complement C3a, an anaphylatoxin generated upon complement C3 activation, with prevalent CVD and markers of subclinical atherosclerosis [i.e. carotid intimamedia thickness (cIMT) and ankle-arm blood-pressure index (AAIx)] in a diabetes-prone population.