Arginine-directed glycation and decreased HDL plasma concentration and functionality

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.

Diabetes Mellitus Is Associated With Reduced High-Density Lipoprotein Sphingosine-1-Phosphate Content and Impaired High-Density Lipoprotein Cardiac Cell Protection

“…Moreover, recent studies have reported that in vivo glycated products derived from MG best differentiate diabetic and nondiabetic HDL. 23,24 In our studies, the consequence of such in vitro glycation was to reduce by 20% to 30% the protective capacity of HDL in both in vitro and by guest on May 11, 2018 http://atvb.ahajournals.org/ Downloaded from ex vivo models of acute oxidative stress. It was linked to compromised activation of Akt, Stat3, and Erk1/2, protein kinases that have key roles in the SAFE (survivor activating factor enhancement) and RISK (reperfusion injury salvage kinase) myocardial prosurvival pathways and that we previously identified as important in HDL-mediated protection of cardiomyocytes.…”

Creatine Is a Scavenger for Methylglyoxal under Physiological Conditions via Formation of N-(4-Methyl-5-oxo-1-imidazolin-2-yl)sarcosine (MG-HCr)

“…In conse-270 quence of the inflexible heterocyclic hydroimidazolone structure, the NOESY experiment 271 showed only cross peaks of the protons of C-2 with C-6 and C-8 with C-9. An additional 1 H-272 14 15 N HMBC experiment resulted in cross peaks of the proton at C-2 with all nitrogen atoms N-273 1, N-4 and N-7, also verifying the heterocyclic hydroimidazolone structure. 274…”

Dicarbonyl stress in cell and tissue dysfunction contributing to ageing and disease

“…MG modification of LDL induced atherogenic transformation to small, dense LDL with increased affinity for arterial walls through binding to heparan sulphate proteoglycans [36]. MG modification of HDL induced restructuring of the HDL particles, increasing density, decreasing stability and plasma half-life in vivo [37]. Chemical inhibition of Glo1induced atherosclerosis in apoE deficient mice [38].…”