title: Adenosine A(2A) receptor activation supports an atheroprotective cholesterol balance in human macrophages and endothelial cells.
abstract: The adenosine A(2A) receptor (A(2A)R) plays an important role in the regulation of inflammatory and immune responses. Our previous work has demonstrated that A(2A)R agonists exhibit atheroprotective effects by increasing expression of reverse cholesterol transport proteins in cultured human macrophages. This study explores the impact of pharmacologic activation/inhibition and gene silencing of A(2A)R on cholesterol homeostasis in both THP-1 human monocytes/macrophages and primary human aortic endothelial cells (HAEC). THP-1 human monocytes/macrophages and HAEC exposed to the A(2A)R-specific agonist ATL313 exhibited upregulation of proteins responsible for cholesterol efflux: the ABCA1 and G1 transporters. Further, activation of A(2A)R led to upregulation of the cholesterol metabolizing enzyme P450 27-hydroxylase, accompanied by intracellular changes in level of oxysterols. We demonstrate that anti-atherogenic properties of A(2A)R activation are not limited to the regulation of lipid efflux in vasculature, but include protection from lipid overload in macrophages, particularly via suppression of the CD36 scavenger receptor. The reduced lipid accumulation manifests directly as a diminution in foam cell transformation. In THP-1 macrophages, either A(2A)R pharmacological blockade or gene silencing promote lipid accumulation and enhance foam cell transformation. Our pre-clinical data provides evidence suggesting that A(2A)R stimulation by ATL313 has the potential to be a viable therapeutic strategy for cardiovascular disease prevention, particularly in patients with elevated risk due to immune/inflammatory disorders.
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: Steven
authors.initials: S
authors.lastname: Carsons
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Littlefield
authors.forename: Jayson M
authors.initials: JM
authors.lastname: Rieger
authors.forename: Robert
authors.initials: R
authors.lastname: Figler
authors.forename: Allison B
authors.initials: AB
authors.lastname: Reiss
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D016133:Polymerase Chain Reaction; D043705:Receptor, Adenosine A2A / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D043705:Receptor, Adenosine A2A; D002784:Cholesterol