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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1046.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Inactivation of the Adenosine A_2A Receptor Protects Apolipoprotein E–Deficient Mice From Atherosclerosis

Huan Wang; Weiyu Zhang; Chuhong Zhu; Christoph Bucher; Bruce R. Blazar; Chunxiang Zhang; Jiang-Fan Chen; Joel Linden; Chaodong Wu; Yuqing Huo

From the Department of Medicine (H.W., W.Z., C.Z., C.B., B.R.B., Y.H.), University of Minnesota, Minneapolis; the Department of Anesthesiology (C.Z.), New Jersey Medical School, University of Medicine & Dentistry of New Jersey, Newark; the Department of Neurology (J.-F.C.), Boston University School of Medicine, Boston, Mass; the Department of Medicine (J.L.), University of Virginia Health System, Charlottesville; and the Department of Nutrition and Food Science (C.W.), Texas A&M University, College Station.

Correspondence to Yuqing Huo, MD, PhD, Cardiovascular Division & Vascular Biology Center, Department of Medicine, University of Minnesota, 420 Delaware St SE, MMC508, Minneapolis, MN 55455. E-mail Yuqing{at}umn.edu

Background— Atherosclerosis is a chronic inflammatory disease of the arterial vessel wall. The A_2A receptor (A_2AR) plays a central role in many antiinflammatory effects of adenosine. However, the role of A_2AR in atherosclerosis is not clear.

Methods and Results— The knockout of A_2AR in apolipoprotein E–deficient (Apoe^–/–/A_2AR^–/–) 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^–/–/A_2AR^–/– mice developed smaller lesions, as did chimeric Apoe^–/– mice lacking A_2AR in bone marrow–derived cells (BMDCs). The lesions of those mice exhibited a low density of foam cells and the homing ability of A_2AR-deficient monocytes did not change. Increased foam cell apoptosis was detected in atherosclerotic lesions of Apoe^–/–/A_2AR^–/– mice. In the absence of A_2AR, macrophages incubated with oxidized LDL or in vivo–formed foam cells also exhibited increased apoptosis. A_2AR 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 A_2AR-deficient foam cells.

Conclusion— Inactivation of A_2AR, especially in BMDCs, inhibits the formation of atherosclerotic leisons, suggesting that A_2AR inactivation may be useful for the treatment of atherosclerosis.

Knockout of A2AR in apolipoprotein E–deficient mice led to an increase in body weight and levels of blood cholesterol and proinflammatory cytokines. However, unexpectedly, A2AR deficiency in mice or bone marrow–derived cells dramatically inhibits atherosclerosis. Increased apoptosis of foam cells is the underlying mechanism for decreased atherosclerosis.

Key Words: atherosclerosis • adenosine receptor • macrophages • apoptosis