title: A2A adenosine receptor stimulation decreases foam cell formation by enhancing ABCA1-dependent cholesterol efflux.
abstract: Immune and inflammatory cells play a critical role in the pathogenesis of atherosclerotic plaques. We have demonstrated that A2ARs inhibit foam cell formation and stimulate production of ABCA1, the primary transporter of lipoproteins. We asked whether the effects of A2ARs on foam cell formation in vitro are mediated by transporters involved in reverse cholesterol transport, ABCA1 and ABCG1. Foam cells were generated from THP-1 cells by incubation with 100 nM PMA for 2 days and incubated with acLDL (50 microg/mL) plus IFN-gamma (500 U/mL) +/- A2AR agonist CGS-21680 (1 microM). Radiolabeled cholesterol (0.2 microCi/ml) was added to cells, and efflux was measured using a liquid scintillation counter. Lentiviral siRNA infection markedly reduces ABCA1 or ABCG1 mRNA in THP-1 cells. Despite diminished ABCG1 expression (KD), CGS-21680 inhibits foam cell formation (81+5% inhibition; P<0.0001 vs. IFN-gamma alone; n=3) but has no effect on foam cell formation in ABCA1 KD cells (5+3% inhibition; P<0.85 vs. IFN-gamma alone; n=3). The A2A agonist increases apoA-I-mediated cholesterol efflux nearly twofold in THP-1-derived macrophages (from 9.5% to 17.5+2.5% [3H]-cholesterol efflux; P<0.0090 vs. control; n=3) but not in ABCA1 KD cells. Activation of Epac, a signaling molecule downstream of the A2AR, increased ABCA1 (23+5%; P<0.0007 vs. control; n=3) and phospho-ABCA1 (13+5%; P<0.0003 vs. control; n=3) protein. These results demonstrate that A2AR occupancy diminishes foam cell formation by stimulating increased reverse cholesterol transport via ABCA1.
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, New York, USA. taiese.bingham@gmail.com
authors.forename: Taiese Crystal
authors.initials: TC
authors.lastname: Bingham
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.forename: Saj
authors.initials: S
authors.lastname: Parathath
authors.forename: Allison B
authors.initials: AB
authors.lastname: Reiss
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Chan
authors.forename: Bruce N
authors.initials: BN
authors.lastname: Cronstein
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists; D000959:Antihypertensive Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D016632:Apolipoprotein A-I / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002273:Carcinogens / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D005487:Foam Cells / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D058908:Adenosine A2 Receptor Agonists; D000959:Antihypertensive Agents; D000998:Antiviral Agents; D016632:Apolipoprotein A-I; D002273:Carcinogens; D020662:Guanine Nucleotide Exchange Factors; D008077:Lipoproteins, LDL; D010627:Phenethylamines; C116122:RAPGEF3 protein, human; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; C032629:acetyl-LDL; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D007371:Interferon-gamma; D002784:Cholesterol; D000241:Adenosine; D013755:Tetradecanoylphorbol Acetate