Glycation of LDL by Methylglyoxal Increases Arterial Atherogenicity - metformin

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Glycation of LDL by Methylglyoxal Increases Arterial Atherogenicity: A

Possible Contributor to Increased Risk of Cardiovascular Disease in

Diabetes. <http://www.ncbi.nlm.nih.gov/pubmed/21617182>

Rabbani N, Godfrey L, Xue M, Shaheen F, Geoffrion M, Milne R, Thornalley PJ.

Diabetes. 2011 Jul;60(7):1973-80. Epub 2011 May 26.

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.

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*/LDL Cholesterol Variant Synthesized by Researchers/*

Heigl on July 11, 2011

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07-11-2011