Inactivation of the Adenosine A2A Receptor Protects Apolipoprotein E–Deficient Mice From Atherosclerosis
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Background— Atherosclerosis is a chronic inflammatory disease of the arterial vessel wall. The A2A receptor (A2AR) plays a central role in many antiinflammatory effects of adenosine. However, the role of A2AR in atherosclerosis is not clear.
Methods and Results— The knockout of A2AR in apolipoprotein E–deficient (Apoe−/−/A2AR−/−) mice led to an increase in body weight and levels of blood cholesterol and proinflammatory cytokines, as well as the inflammation status of atherosclerotic lesions. Unexpectedly, Apoe−/−/A2AR−/− mice developed smaller lesions, as did chimeric Apoe−/− mice lacking A2AR in bone marrow–derived cells (BMDCs). The lesions of those mice exhibited a low density of foam cells and the homing ability of A2AR-deficient monocytes did not change. Increased foam cell apoptosis was detected in atherosclerotic lesions of Apoe−/−/A2AR−/− mice. In the absence of A2AR, macrophages incubated with oxidized LDL or in vivo–formed foam cells also exhibited increased apoptosis. A2AR deficiency in foam cells resulted in an increase in p38 mitogen–activated protein kinase (MAPK) activity. Inhibition of p38 phosphorylation abrogated the increased apoptosis of A2AR-deficient foam cells.
Conclusion— Inactivation of A2AR, especially in BMDCs, inhibits the formation of atherosclerotic leisons, suggesting that A2AR inactivation may be useful for the treatment of atherosclerosis.