title: Resveratrol mediates anti-atherogenic effects on cholesterol flux in human macrophages and endothelium via PPARγ and adenosine.
abstract: Resveratrol is a bioactive molecule used in dietary supplements and herbal medicines and consumed worldwide. Known cardioprotective and anti-inflammatory properties of resveratrol have spurred investigation of the mechanisms involved. The present study explored potential atheroprotective actions of resveratrol on cholesterol metabolism in cells of the arterial wall, including human macrophages and arterial endothelium. Using QRT-PCR and Western blotting techniques, we measured expression of the proteins involved in reverse cholesterol transport (ABCA1, ABCG1 and SR-B1) and the scavenger receptors responsible for uptake of modified cholesterol (CD36, SR-A1 and LOX-1). We analyzed the effect of resveratrol on apoA-1-and HDL-mediated cholesterol efflux in human THP-1 macrophages. The effect of resveratrol on oxLDL internalization and foam cell formation were evaluated using confocal and light microscopy. Our data indicate that resveratrol regulates expression of major proteins involved in cholesterol transport, promotes apoA-1 and HDL-mediated efflux, downregulates oxLDL uptake and diminishes foam cell formation. Mechanistically, resveratrol effects were dependent upon PPAR-γ and adenosine 2A receptor pathways. For the first time we demonstrate that resveratrol regulates expression of the cholesterol metabolizing enzyme cytochrome P450 27-hydroxylase, providing efficient cholesterol elimination via formation of oxysterols. This study establishes that resveratrol attenuates lipid accumulation in cultured human macrophages via effects on cholesterol transport. Further in vivo studies are needed to determine whether resveratrol may be an additional resource available to reduce lipid deposition and atherosclerosis in humans.
authors.affiliation: Winthrop Research Institute, Department of Medicine, Winthrop University Hospital, 222 Station Plaza, North, Suite 511B, Mineola, NY 11501, USA. IVoloshyna@Winthrop.org
authors.forename: Iryna
authors.initials: I
authors.lastname: Voloshyna
authors.forename: Ofek
authors.initials: O
authors.lastname: Hai
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Littlefield
authors.forename: Steven
authors.initials: S
authors.lastname: Carsons
authors.forename: Allison B
authors.initials: AB
authors.lastname: Reiss
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D001692:Biological Transport / Q000187:drug effects; D018955:CD36 Antigens / Q000235:genetics; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism*; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism; D005487:Foam Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D043683:Receptors, Adenosine A2 / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D018955:CD36 Antigens; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D047495:PPAR gamma; D043683:Receptors, Adenosine A2; D013267:Stilbenes; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D000241:Adenosine; D000077185:Resveratrol