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Adenosine A 2A receptor occupancy stimulates expression of proteins involved in reverse cholesterol transport and inhibits foam cell formation in macrophages
Author(s) -
Reiss Allison B.,
Rahman Mohammad M.,
Chan Edwin S. L.,
Montesinos M. Carmen,
Awadallah Nahel W.,
Cronstein Bruce N.
Publication year - 2004
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0204107
Subject(s) - foam cell , adenosine a2a receptor , reverse cholesterol transport , proinflammatory cytokine , adenosine , biology , inflammasome , adenosine receptor , pharmacology , cholesterol , microbiology and biotechnology , endocrinology , medicine , biochemistry , receptor , agonist , inflammation , immunology , lipoprotein
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′‐triphosphat‐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 2A R) minimizes early atherosclerotic changes in arteries following injury. We therefore asked whether A 2A R occupancy affects macrophage foam cell formation in response to IC and the cytokine interferon‐γ. We found that the selective A 2A 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 2A R 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 2A R 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 2A R‐deficient mice. Agents that increase foam cell formation also down‐regulate cholesterol 27‐hydroxylase and ABCA1 expression. Therefore, we determined the effect of A 2A R occupancy on expression of these reverse cholesterol transport (RCT) proteins and found that A 2A R 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.