Published online before print June 14, 2004

This Article Full Text (Reprint (PDF)) All Versions of this Article: jlb.0204107v1 76/3/727    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Reiss, A. B. Articles by Cronstein, B. N. Search for Related Content PubMed PubMed Citation Articles by Reiss, A. B. Articles by Cronstein, B. N.

© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0204107

Received for publication February 23, 2004.
Revised April 14, 2004.
Accepted for publication April 26, 2004.

Article

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 Medical Center, New York

^@ To whom correspondence should be addressed. E-mail: reissa01{at}popmail.med.nyu.edu.

Abstract

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<sub>2A</sub> receptor (A<sub>2A</sub>R) minimizes early atherosclerotic changes in arteries following injury. We therefore asked whether A<sub>2A</sub>R occupancy affects macrophage foam cell formation in response to IC and the cytokine interferon-. We found that the selective A<sub>2A</sub>R 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. It is more important that these findings suggest a novel approach to the development of agents that prevent progression of atherosclerosis.

Key Words: atherosclerosis • cholesterol 27-hydroxylase • ABCA1

This article has been cited by other articles:

				S. Gessi, E. Fogli, V. Sacchetto, S. Merighi, K. Varani, D. Preti, E. Leung, S. MacLennan, and P. A. Borea Adenosine Modulates HIF-1{alpha}, VEGF, IL-8, and Foam Cell Formation in a Human Model of Hypoxic Foam Cells Arterioscler Thromb Vasc Biol, January 1, 2010; 30(1): 90 - 97. [Abstract] [Full Text] [PDF]

				K. E. Barnholt, R. S. Kota, H. H. Aung, and J. C. Rutledge Adenosine Blocks IFN-{gamma}-Induced Phosphorylation of STAT1 on Serine 727 to Reduce Macrophage Activation J. Immunol., November 15, 2009; 183(10): 6767 - 6777. [Abstract] [Full Text] [PDF]

				H. Wang, W. Zhang, C. Zhu, C. Bucher, B. R. Blazar, C. Zhang, J.-F. Chen, J. Linden, C. Wu, and Y. Huo Inactivation of the Adenosine A2A Receptor Protects Apolipoprotein E-Deficient Mice From Atherosclerosis Arterioscler Thromb Vasc Biol, July 1, 2009; 29(7): 1046 - 1052. [Abstract] [Full Text] [PDF]

				R. Ohashi, H. Mu, X. Wang, Q. Yao, and C. Chen Reverse cholesterol transport and cholesterol efflux in atherosclerosis QJM, December 1, 2005; 98(12): 845 - 856. [Abstract] [Full Text] [PDF]

				A. Daugherty, N. R. Webb, D. L. Rateri, and V. L. King Thematic review series: The Immune System and Atherogenesis. Cytokine regulation of macrophage functions in atherogenesis J. Lipid Res., September 1, 2005; 46(9): 1812 - 1822. [Abstract] [Full Text] [PDF]