Inactivation of the adenosine A2A receptor protects apolipoprotein E-deficient mice from atherosclerosis

Abstract

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. © 2009 American Heart Association, Inc.