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Published online before print June 14, 2004

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(Journal of Leukocyte Biology. 2004;76:727-734.)
© 2004 by Society for Leukocyte Biology

Adenosine A_2A receptor occupancy stimulates expression of proteins involved in reverse cholesterol transport and inhibits foam cell formation in macrophages

Department of Medicine, New York University School of Medicine, New York

¹ Correspondence: Department of Medicine, New Bellevue 16N1, New York University Medical Center, 550 First Ave., New York, NY 10016. E-mail: reissa01{at}popmail.med.nyu.edu

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 A_2A receptor (A_2AR) minimizes early atherosclerotic changes in arteries following injury. We therefore asked whether A_2AR occupancy affects macrophage foam cell formation in response to IC and the cytokine interferon-. We found that the selective A_2AR 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 A_2AR 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 A_2AR 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 A_2AR-deficient mice. Agents that increase foam cell formation also down-regulate cholesterol 27-hydroxylase and ABCA1 expression. Therefore, we determined the effect of A_2AR occupancy on expression of these reverse cholesterol transport (RCT) proteins and found that A_2AR 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.

Key Words: atherosclerosis • cholesterol 27-hydroxylase • ABCA1

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