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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:e174.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Bone Marrow–Derived Monocyte Chemoattractant Protein-1 Receptor CCR2 Is Critical in Angiotensin II–Induced Acceleration of Atherosclerosis and Aneurysm Formation in Hypercholesterolemic Mice

Minako Ishibashi; Kensuke Egashira; Qingwei Zhao; Ken-ichi Hiasa; Kisho Ohtani; Yoshiko Ihara; Israel F. Charo; Shinobu Kura; Teruhisa Tsuzuki; Akira Takeshita; Kenji Sunagawa

From the Department of Cardiovascular Medicine (M.I., K.E., Q.Z., K.H., K.O., Y.I., A.T., K.S.) and the Department of Medical Biophysics and Radiation Biology (S.K., T.T.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and the Gladstone Institute of Cardiovascular Disease (I.F.C.), San Francisco, Calif.

Correspondence to Dr Kensuke Egashira, Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail egashira{at}cardiol.med.kyushu-u.ac.jp

Angiotensin II (Ang II) is implicated in atherogenesis by activating inflammatory responses in arterial wall cells. Ang II accelerates the atherosclerotic process in hyperlipidemic apoE–/– mice by recruiting and activating monocytes. Monocyte chemoattractant protein-1 (MCP-1) controls monocyte-mediated inflammation through its receptor, CCR2. The roles of leukocyte-derived CCR2 in the Ang II-induced acceleration of the atherosclerotic process, however, are not known. We hypothesized that deficiency of leukocyte-derived CCR2 suppresses Ang II-induced atherosclerosis.

Methods and Results— A bone marrow transplantation technique (BMT) was used to develop apoE–/– mice with and without deficiency of CCR2 in leukocytes (BMT-apoE–/–CCR2+/+ and BMT-apoE–/–CCR2–/– mice). Compared with BMT-apoE–/–CCR2+/+ mice, Ang II-induced increases in atherosclerosis plaque size and abdominal aortic aneurysm formation were suppressed in BMT-apoE–/–CCR2–/– mice. This suppression was associated with a marked decrease in monocyte-mediated inflammation and inflammatory cytokine expression.

Conclusion— Leukocyte-derived CCR2 is critical in Ang II-induced atherosclerosis and abdominal aneurysm formation. The present data suggest that vascular inflammation mediated by CCR2 in leukocytes is a reasonable target of therapy for treatment of atherosclerosis.

We determined the role of leukocyte-derived CCR2 (the receptor for monocyte chemoattractant protein-1) in the angiotensin II (Ang II)-induced acceleration of atherosclerotic process. We show that Ang II-induced atherosclerotic process was blunted in hypercholesterolemic apoE–/– mice with deficiency of leukocyte-derived CCR2. These data suggest that leukocyte-derived CCR2 is critical in Ang II-induced atherosclerosis.

Key Words: atherosclerosis • angiotensin II • inflammation • leukocytes

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