Rabbani, Naila, Godfrey, L. (Lisa), Xue, Mingzhan, Shaheen, Fozia, Geoffrion, M., Milne, Ross and Thornalley, Paul J.. (2011) Glycation of LDL by methylglyoxal increases arterial atherogenicity : a possible contributor to increased risk of cardiovascular disease in diabetes. Diabetes, Vol.60 (No.7). pp. 1973-1980. ISSN 0012-1797

Full text not available from this repository.

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 (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. RESULTS MGmin-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. 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.

Item Type:	Journal Article
Subjects:	Q Science > QP Physiology R Medicine > RC Internal medicine
Divisions:	Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Glycosylation, Low density lipoproteins, Cardiovascular system -- Diseases, Diabetes -- Risk factors
Journal or Publication Title:	Diabetes
Publisher:	American Diabetes Association
ISSN:	0012-1797
Date:	2011
Volume:	Vol.60
Number:	No.7
Page Range:	pp. 1973-1980
Identification Number:	10.2337/db11-0085
Status:	Peer Reviewed
Publication Status:	Published
Funder:	British Heart Foundation, Heart and Stroke Foundation of Canada
Grant number:	T6110 (HSFC)
URI:	http://wrap.warwick.ac.uk/id/eprint/39491

Data sourced from Thomson Reuters' Web of Knowledge

Request changes to a record

Actions (login required)

View Item