ATP-binding cassette transporter 1 participates in LDL oxidation by artery wall cells.
OBJECTIVE
We have previously reported that products of the lipoxygenase pathway, hydroperoxyoctadecadienoic acid and hydroperoxyeicosatetraenoic acid, as well as cholesterol linoleate hydroperoxides, collectively termed seeding molecules, are removed by apolipoprotein A-I (apoA-I) from the artery wall cells and render low density lipoprotein (LDL) resistant to oxidation by human artery wall cells. The mechanisms by which oxidized lipids are transported and/or transferred to lipoproteins and the pathways by which apoA-I facilitates their removal remain unclear. ATP-binding cassette transporter 1 (ABCA1) is known to facilitate the release of cellular phospholipids and cholesterol from the plasma membrane to apoA-I and high density lipoprotein. Therefore, we evaluated whether ABCA1 participates in LDL oxidation.


RESULTS
In this report, we show that (1) chemical inhibitors of ABCA1 function, glyburide and DIDS, block artery wall cell-mediated oxidative modification of LDL, (2) inhibition of ABCA1 with the use of antisense (but not sense) oligonucleotides prevents LDL-induced lipid hydroperoxide formation and LDL-induced monocyte chemotactic activity by the artery wall cells, and (3) oxysterols that induce ABCA1 expression, such as 22(R)hydroxycholesterol, enhance cell-mediated LDL oxidation. Furthermore, we also show that 22(R)hydroxycholesterol induces the production of reactive oxygen species in the artery wall cells, which can be removed by incubating the artery wall cells with apoA-I.


CONCLUSIONS
Our data suggest that ABCA1 plays an important role in artery wall cell-mediated modification/oxidation of LDL by modulating the release of reactive oxygen species from artery wall cells that are necessary for LDL oxidation.
Reddy
Srinivasa T
ST
Atherosclerosis Research Unit, Division of Cardiology, Department of Medicine, University of California, Los Angeles 90095, USA. sreddy@mednet.ucla.edu
Hama
Susan
S
Ng
Carey
C
Grijalva
Victor
V
Navab
Mohamad
M
Fogelman
Alan M
AM
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D001011:Aorta / Q000166:cytology; D016632:Apolipoprotein A-I / Q000494:pharmacology; D001158:Arteries / Q000166:cytology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D006888:Hydroxycholesterols; D008077:Lipoproteins, LDL; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C099252:oxidized low density lipoprotein; C003585:22-hydroxycholesterol; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D005905:Glyburide