Glycation of LDL by Methylglyoxal Increases Arterial Atherogenicity A Possible Contributor to Increased Risk of Cardiovascular Disease in Diabetes

摘要

OBJECTIVE-To study whether modification of LDL by methylglyoxal (MG), a potent arginine-directed glyeating 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 (MGmin-LDL) as occurs in vivo. Atherogenic characteristics of MGn^-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 apolipopro-tein B100 (apoBlOO) modification was investigated by mass spec-trometric 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 proteogly-cans, 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 apoBlOO modification in MG_(min)-LDL. A computed structural model predicted that MG modification of apoBlOO induces distortion, increasing exposure of the iV-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.