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Diabetes. 2011 Jul;60(7):1973-80. doi: 10.2337/db11-0085. Epub 2011 May 26.

Glycation of LDL by methylglyoxal increases arterial atherogenicity: a possible contributor to increased risk of cardiovascular disease in diabetes.

Author information

  • 1Warwick Medical School, Clinical Sciences Research Institute, University of Warwick, University Hospital, Coventry, UK. n.rabbani@warwick.ac.uk

Abstract

OBJECTIVE:

To 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 METHODS:

Human LDL was isolated and modified by MG in vitro to minimal extent (MG(min)-LDL) as occurs in vivo. Atherogenic characteristics of MG(min)-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.

RESULTS:

MG(min)-LDL contained 1.6 molar equivalents of MG modification-mostly hydroimidazolone-as found in vivo. MG(min)-LDL had decreased particle size, increased binding to proteoglycans, and increased aggregation in vitro. Cell culture studies showed that MG(min)-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 MG(min)-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 MG(min)-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.

CONCLUSIONS:

MG 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.

© 2011 by the American Diabetes Association.

PMID:
21617182
[PubMed - indexed for MEDLINE]
PMCID:
PMC3121424
Free PMC Article

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