title: Glycation of LDL by methylglyoxal increases arterial atherogenicity: a possible contributor to increased risk of cardiovascular disease in diabetes.
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.
  
  
  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.
authors: Warwick Medical School, Clinical Sciences Research Institute, University of Warwick, University Hospital, Coventry, UK. n.rabbani@warwick.ac.uk
authors: Naila
authors: N
authors: Rabbani
authors: Lisa
authors: L
authors: Godfrey
authors: Mingzhan
authors: M
authors: Xue
authors: Fozia
authors: F
authors: Shaheen
authors: Michèle
authors: M
authors: Geoffrion
authors: Ross
authors: R
authors: Milne
authors: Paul J
authors: PJ
authors: Thornalley
references: Diabetes. 2003 Aug;52(8):2110-20
references: 12882930
references: Diabetes. 2006 Aug;55(8):2238-44
references: 16873686
references: Proc Natl Acad Sci U S A. 1990 Jul;87(14):5523-7
references: 2115173
references: Cardiovasc Drugs Ther. 2008 Jun;22(3):215-24
references: 18288595
references: Diabet Med. 2003 Jul;20(7):563-7
references: 12823238
references: Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):2507-14
references: 9409221
references: J Lipid Res. 2002 Sep;43(9):1363-79
references: 12235168
references: Nature. 2002 Jun 13;417(6890):750-4
references: 12066187
references: Clin Sci (Lond). 1994 Jul;87(1):21-9
references: 8062515
references: J Biol Chem. 1977 Oct 25;252(20):7279-87
references: 198407
references: Diabetologia. 2004 Dec;47(12):2235-46
references: 15662560
references: J Lipid Res. 1996 Dec;37(12):2638-49
references: 9017515
references: Arterioscler Thromb Vasc Biol. 1999 Oct;19(10):2422-30
references: 10521372
references: J Biol Chem. 2002 Aug 30;277(35):32228-33
references: 12070165
references: Biochemistry. 1998 Sep 15;37(37):12867-74
references: 9737865
references: Diabetes Res Clin Pract. 2007 Oct;78(1):34-41
references: 17374417
references: Clin Endocrinol (Oxf). 2009 Jun;70(6):870-5
references: 18771560
references: J Nutr Biochem. 2002 Jun;13(6):330-336
references: 12088798
references: Mol Nutr Food Res. 2007 Sep;51(9):1107-10
references: 17854008
references: Methods Enzymol. 1983;98:241-60
references: 6321901
references: Arterioscler Thromb Vasc Biol. 2009 Apr;29(4):431-8
references: 19299327
references: Diabetes. 2004 Jul;53(7):1813-23
references: 15220206
references: Amino Acids. 2012 May;42(5):1627-39
references: 21384133
references: J Lipid Res. 1998 Jun;39(6):1263-73
references: 9643358
references: Int Angiol. 2006 Mar;25(1):4-9
references: 16520717
references: Circulation. 2004 Aug 3;110(5):637-41
references: 15289389
references: J Lipid Res. 2004 Feb;45(2):272-80
references: 14563829
references: J Lipid Res. 2010 Aug;51(8):2445-53
references: 20386060
references: Arterioscler Thromb. 1992 May;12(5):569-83
references: 1576119
references: Int J Clin Pract. 2010 Nov;64(12):1632-42
references: 20831734
references: Arterioscler Thromb. 1993 May;13(5):712-9
references: 8485123
references: Biochem J. 1988 Sep 15;254(3):751-5
references: 3196289
references: Eur J Pharmacol. 1998 Jun 12;351(1):79-83
references: 9698208
references: Mol Cell Proteomics. 2005 Sep;4(9):1350-7
references: 15970583
references: J Lipid Res. 1981 Feb;22(2):236-44
references: 7240955
references: Arch Biochem Biophys. 2003 Nov 1;419(1):31-40
references: 14568006
references: J Lipid Res. 2000 Nov;41(11):1703-14
references: 11060340
references: Diabetes. 1999 Jan;48(1):198-202
references: 9892243
references: Mol Aspects Med. 1993;14(4):287-371
references: 8277832
references: Ann N Y Acad Sci. 2005 Jun;1043:111-7
references: 16037229
references: Circulation. 2004 Mar 30;109(12):1536-42
references: 15023892
references: J Biol Chem. 2005 Nov 11;280(45):37449-54
references: 16147996
references: J Clin Endocrinol Metab. 2003 Oct;88(10):4525-32
references: 14557416
references: Diabetes Res Clin Pract. 2001 Feb;51(2):107-14
references: 11165690
references: Atherosclerosis. 1996 Jun;123(1-2):43-56
references: 8782836
references: J Lipid Res. 1998 Jan;39(1):85-102
references: 9469589
references: Am J Pathol. 1998 Feb;152(2):533-46
references: 9466580
references: Diabetes. 2010 Apr;59(4):1038-45
references: 20068133
references: J Biol Chem. 1996 Apr 19;271(16):9595-602
references: 8621634