Abstract
Background/Objectives:Decreased plasma concentration of high-density lipoprotein cholesterol (HDL-C) is a risk factor linked to increased risk of cardiovascular disease (CVD). Decreased anti-atherogenic properties of HDL are also implicated in increased CVD risk. The cause is unknown but has been linked to impaired glucose tolerance. The aim of this study was to quantify the modification of HDL by methylglyoxal and related dicarbonyls in healthy people and patients with type 2 diabetes characterise structural, functional and physiological consequences of the modification and predict the importance in high CVD risk groups.Subjects/Methods:Major fractions of HDL, HDL2 and HDL3 were isolated from healthy human subjects and patients with type 2 diabetes and fractions modified by methylglyoxal and related dicarbonyl metabolites quantified. HDL2 and HDL3 were glycated by methylglyoxal to minimum extent in vitro and molecular, functional and physiological characteristics were determined. A one-compartment model of HDL plasma clearance was produced including formation and clearance of dicarbonyl-modified HDL.Results:HDL modified by methylglyoxal and related dicarbonyl metabolites accounted for 2.6% HDL and increased to 4.5% in patients with type 2 diabetes mellitus (T2DM). HDL2 and HDL3 were modified by methylglyoxal to similar extents in vitro. Methylglyoxal modification induced re-structuring of the HDL particles, decreasing stability and plasma half-life in vivo. It occurred at sites of apolipoprotein A-1 in HDL linked to membrane fusion, intramolecular bonding and ligand binding. Kinetic modelling of methylglyoxal modification of HDL predicted a negative correlation of plasma HDL-C with methylglyoxal-modified HDL. This was validated clinically. It also predicted that dicarbonyl modification produces 2–6% decrease in total plasma HDL and 5–13% decrease in functional HDL clinically.Conclusions:These results suggest that methylglyoxal modification of HDL accelerates its degradation and impairs its functionality in vivo, likely contributing to increased risk of CVD—particularly in high CVD risk groups.
Highlights
The risk of cardiovascular disease (CVD) increases with age, diabetes and renal failure.[1,2] Residual high risk of CVD in the general population suggests that CVD development is linked to risk factors unaddressed by current therapy
Methylglyoxal-derived MG-H1 was a major adduct of lipoprotein of HDL2 and HDL3 isolated from healthy human subjects
HDL2 and HDL3 were modified by similar hydroimidazolone advanced glycation endproduct (AGE) formed by glycation with related dicarbonyl metabolites, glyoxal and 3-deoxyglucosone
Summary
The risk of cardiovascular disease (CVD) increases with age, diabetes and renal failure.[1,2] Residual high risk of CVD in the general population suggests that CVD development is linked to risk factors unaddressed by current therapy. In large prospective studies the risk of coronary heart disease was linked to ApoA1 and impaired glycemic control.[1] Reviewing metabolic factors linked to dysglycemia, methylglyoxal—a reactive metabolite formed by the degradation of triosephosphates and metabolised by the glutathione-dependent glyoxalase system6—emerged as a potential mediator of HDL dysfunction. Plasma concentrations of methylglyoxal are increased by shortterm and persistent increases in glucose concentration7,8 —exacerbated by impairment of glyoxalase 1 expression and activity in oxidative stress, vascular inflammation and aging.[6,9] Protein modification by methylglyoxal is relatively rapid and increases in aging, with further marked increases in diabetes and renal failure.[10,11,12] Glycation of proteins by methylglyoxal is directed toward arginine residues, forming mainly the hydroimidazolone MG-H1—a quantitatively and functionally important advanced glycation endproduct (AGE) in physiological systems 13 (Figure 1). We sought to characterise the extent of HDL modification by methylglyoxal and functional consequences in healthy people and predict the importance of this in high CVD risk groups, including patients with type 2 diabetes mellitus (T2DM)
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