A2A adenosine receptor stimulation decreases foam cell formation by enhancing ABCA1‐dependent cholesterol efflux

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: atherosclerosis;    inflammation;    macrophages;   

DOI  :  10.1189/jlb.0709513

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Immuneandinflammatorycellsplayacriticalroleinthepathogenesisofatheroscleroticplaques.WehavedemonstratedthatA2ARsinhibitfoamcellformationandstimulateproductionofABCA1,theprimarytransporteroflipoproteins.WeaskedwhethertheeffectsofA2ARsonfoamcellformationinvitroaremediatedbytransportersinvolvedinreversecholesteroltransport,ABCA1andABCG1.FoamcellsweregeneratedfromTHP‐1cellsbyincubationwith100nMPMAfor2daysandincubatedwithacLDL(50μg/mL)plusIFN‐γ(500U/mL)±A2ARagonistCGS‐21680(1μM).Radiolabeledcholesterol(0.2μCi/ml)wasaddedtocells,andeffluxwasmeasuredusingaliquidscintillationcounter.LentiviralsiRNAinfectionmarkedlyreducesABCA1orABCG1mRNAinTHP‐1cells.DespitediminishedABCG1expression(KD),CGS‐21680inhibitsfoamcellformation(81+5%inhibition;P<0.0001vs.IFN‐γalone;n=3)buthasnoeffectonfoamcellformationinABCA1KDcells(5+3%inhibition;P<0.85vs.IFN‐γalone;n=3).TheA2AagonistincreasesapoA‐I‐mediatedcholesteroleffluxnearlytwofoldinTHP‐1‐derivedmacrophages(from9.5%to17.5+2.5%[3H]‐cholesterolefflux;P<0.0090vs.control;n=3)butnotinABCA1KDcells.ActivationofEpac,asignalingmoleculedownstreamoftheA2AR,increasedABCA1(23+5%;P<0.0007vs.control;n=3)andphospho‐ABCA1(13+5%;P<0.0003vs.control;n=3)protein.TheseresultsdemonstratethatA2ARoccupancydiminishesfoamcellformationbystimulatingincreasedreversecholesteroltransportviaABCA1...

【 授权许可】

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