2-(2-(4-chlorophenyl)ethoxy)adenosine and Arteriosclerosis

Transport of cholesterol out of macrophages is critical for prevention of foam cell formation, the first step in the pathogenesis of atherosclerosis. Proteins involved in this process include cholesterol 27-hydroxylase and adenosine 5'-triphosphate-binding cassette transporter A1 (ABCA1). Proinflammatory cytokines and immune complexes (IC) down-regulate cholesterol 27-hydroxylase and impede cholesterol efflux from macrophages, leading to foam cell formation. Prior studies have suggested occupancy of the anti-inflammatory adenosine A2A receptor (A2AR) minimizes early atherosclerotic changes in arteries following injury. We therefore asked whether A2AR occupancy affects macrophage foam cell formation in response to IC and the cytokine interferon-gamma. We found that the selective A2AR agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido-adenosine (CGS-21680) inhibited foam cell formation in stimulated THP-1 human macrophages, and the effects of CGS-21680 were reversed by the selective A2AR antagonist 4-(2-[7-amino-2-(2-furyl) [1, 2, 4]triazolo[2,3-a] [1, 3, 5]triazin-5-ylamino]ethyl)phenol. In confirmation of the role of A2AR in prevention of foam cell formation, CGS-21680 also inhibited foam cell formation in cultured murine peritoneal macrophages but did not affect foam cell formation in A2AR-deficient mice. Agents that increase foam cell formation also down-regulate cholesterol 27-hydroxylase and ABCA1 expression. Therefore, we determined the effect of A2AR occupancy on expression of these reverse cholesterol transport (RCT) proteins and found that A2AR occupancy stimulates expression of message for both proteins. These results indicate that one mechanism for the antiatherogenic effects of adenosine is stimulation of the expression of proteins involved in RCT. These findings suggest a novel approach to the development of agents that prevent progression of atherosclerosis.

Topics: Adenosine; Adenosine A2 Receptor Agonists; Adenosine A2 Receptor Antagonists; Animals; Arteriosclerosis; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters; Carrier Proteins; Cell Differentiation; Cholestanetriol 26-Monooxygenase; Cholesterol; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Down-Regulation; Foam Cells; Gene Expression Regulation, Enzymologic; Humans; Macrophages; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Phenethylamines; Receptor, Adenosine A2A; RNA, Messenger; Steroid Hydroxylases; Triazines; Triazoles; Up-Regulation