Glycation of LDL by Methylglyoxal Increases Arterial Atherogenicity

Abstract

OBJECTIVETo study whether modification of LDL by methylglyoxal (MG), a potent arginine-directed glycating agent that is increased in diabetes, is associated with increased atherogenicity.RESEARCH DESIGN AND METHODSHuman LDL was isolated and modified by MG in vitro to minimal extent (MGmin-LDL) as occurs in vivo. Atherogenic characteristics of MGmin-LDL were characterized: particle size, proteoglycan-binding, susceptibility to aggregation, LDL and non-LDL receptor–binding, and aortal deposition. The major site of modification of apolipoprotein B100 (apoB100) modification was investigated by mass spectrometric peptide mapping.RESULTSMGmin-LDL contained 1.6 molar equivalents of MG modification—mostly hydroimidazolone—as found in vivo. MGmin-LDL had decreased particle size, increased binding to proteoglycans, and increased aggregation in vitro. Cell culture studies showed that MGmin-LDL was bound by the LDL receptor but not by the scavenger receptor and had increased binding affinity for cell surface heparan sulfate–containing proteoglycan. Radiotracer studies in rats showed that MGmin-LDL had a similar fractional clearance rate in plasma to unmodified LDL but increased partitioning onto the aortal wall. Mass spectrometry peptide mapping identified arginine-18 as the hotspot site of apoB100 modification in MGmin-LDL. A computed structural model predicted that MG modification of apoB100 induces distortion, increasing exposure of the N-terminal proteoglycan–binding domain on the surface of LDL. This likely mediates particle remodeling and increases proteoglycan binding.CONCLUSIONSMG modification of LDL forms small, dense LDL with increased atherogenicity that provides a new route to atherogenic LDL and may explain the escalation of cardiovascular risk in diabetes and the cardioprotective effect of metformin.

Plasma advanced glycation end products (AGEs) and NF-κB activity are independent determinants of diastolic and pulse pressure

“…Experimental evidence has shown that AGE accumulation affords structural and functional changes in the cardiovascular system and results in myocardial relaxation abnormalities, atherosclerotic plaque formation, large artery stiffening and endothelial dysfunction [4,[19][20][21][22]. In the vessel wall, AGEs form covalent crosslinks with matrix proteins, which increases vessel rigidity, trap lipoproteins within the arterial wall and disrupts their clearance [23][24][25].…”

Aging: Drugs to Eliminate Methylglyoxal, a Reactive Glucose Metabolite, and Advanced Glycation Endproducts

“…We have shown that fructose-fed Sprague-Dawley rats had significantly elevated serum MG and blood pressure, and increased levels of MG, hydrogen peroxide and the MG-derived AGE, CEL, in the aorta, all of which were attenuated by metformin [65]. Metformin has been proposed to protect against MG-induced increased atherogenicity of low density lipoprotein (LDL) [176]. The use of metformin as a MG scavenger and AGEs inhibitor is limited, and hopefully more studies showing its anti-MG, anti-AGEs effectiveness will promote its use for this purpose.…”

Dyslipidemia and Cardiovascular Disease

“…In elderly, the activity of the enzyme for detoxification of MGmin-LDL is reduced. They (Rabbani et al, 2011) also showed that metformin can block the glycation processes which might explain the cardioprotective effects of this drug. This discovery could lead to invention of new treatments for CVD prevention especially in type 2 diabetics and the elderly subjects.…”

“…After LDL particle concentration adjustment, LDL size was no longer associated with CHD. Recently, some scientists from the University of Warwick in UK discovered a modified form of LDL, MGmin-LDL, also called super-sticky LDL, or very-bad LDL, that promotes CVD (Rabbani et al, 2011). High levels of this lipid are more common in diabetics and elderly patients.…”

“…This may explain the high frequency of CVD in diabetics and elderly patients. Rabbani et al (Rabbani et al, 2011) found that secondary to hyperglycemia, LDL is glycated with methylglyoxal (MG) and makes a type of LDL with smaller, stickier and more atherogenic LDL than normal LDL. The MGmin-LDL can help to build fatty plaques.…”