Advanced glycation of apolipoprotein A-I impairs its anti-atherogenic properties.
OBJECTIVE
AGE contribute to the pathogenesis of diabetic complications, including dyslipidaemia and atherosclerosis. However, the precise mechanisms remain to be established. In the present study, we examined whether AGE modification of apolipoprotein A-I (apoA-I) affects its functionality, thus altering its cardioprotective profile.


METHODS
The ability of AGE-modified apoA-I to facilitate cholesterol and phospholipid efflux, stabilise ATP-binding cassette transporter A1 (ABCA1) and inhibit expression of adhesion molecules in human macrophages and monocytes was studied.


RESULTS
The ability of AGE-modified apoA-I to promote cholesterol efflux from THP-1 macrophages, isolated human monocytes and from ABCA1-transfected HeLa cells was significantly reduced (>70%) compared with unmodified apoA-I. This effect was reversed by preventing AGE formation with aminoguanidine or reversing AGE modification using the cross-link breaker alagebrium chloride. AGE-modification of HDL also reduced its capacity to promote cholesterol efflux. AGE-apoA-I was also less effective than apoA-I in stabilising ABCA1 in THP-1 cells as well as in inhibiting expression of CD11b in human monocytes.


CONCLUSIONS
AGE modification of apoA-I considerably impairs its cardioprotective, antiatherogenic properties, including the ability to promote cholesterol efflux, stabilise ABCA1 and inhibit the expression of adhesion molecules. These findings provide a rationale for targeting AGE in the management of diabetic dyslipidaemia.
Hoang
A
A
Baker Heart Research Institute, St Kilda Road Central, Melbourne, Victoria 8008, Australia.
Murphy
A J
AJ
Coughlan
M T
MT
Thomas
M C
MC
Forbes
J M
JM
O'Brien
R
R
Cooper
M E
ME
Chin-Dusting
J P F
JP
Sviridov
D
D
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016632:Apolipoprotein A-I / Q000378:metabolism*; D050197:Atherosclerosis / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D039481:CD11b Antigen / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006031:Glycosylation / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008075:Lipoproteins, HDL / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D012266:Ribose / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D014162:Transfection
D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D039481:CD11b Antigen; D017127:Glycation End Products, Advanced; D006146:Guanidines; D008075:Lipoproteins, HDL; D010743:Phospholipids; D013844:Thiazoles; D012266:Ribose; D002784:Cholesterol; C406794:alagebrium; C004479:pimagedine