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

Abstract

Abstract-Angiotensin II (Ang II) is implicated in atherogenesis by activating inflammatory responses in arterial wall cells.Ang II accelerates the atherosclerotic process in hyperlipidemic apoEϪ/Ϫ 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 apoEϪ/Ϫ mice with and without deficiency of CCR2 in leukocytes (BMT-apoEϪ/ϪCCR2ϩ/ϩ and BMT-apoEϪ/ϪCCR2Ϫ/Ϫ mice). Compared with BMT-apoEϪ/ϪCCR2ϩ/ϩ mice, Ang II-induced increases in atherosclerosis plaque size and abdominal aortic aneurysm formation were suppressed in BMT-apoEϪ/ϪCCR2Ϫ/Ϫ 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. (Arterioscler Thromb Vasc Biol. 2003;24:e174-e178.)Key Words: atherosclerosis Ⅲ angiotensin II Ⅲ inflammation Ⅲ leukocytes C hronic inflammatory processes have an important role in atherosclerotic plaque progression, destabilization, and subsequent rupture/thrombosis, resulting in acute coronary syndrome. 1,2 Therefore, identification of the critical inflammatory pathway involved in atherosclerotic plaque progression and destabilization might aid in the development of novel therapeutic strategies to reduce atherothrombotic events.The renin-angiotensin system is now recognized as an important therapeutic target of atherosclerotic vascular disease. 3,4 Angiotensin II (Ang II) induces the production of reactive oxidative species and stimulates the expression of adhesion molecules (vascular cell adhesion molecule-1) and chemokines (monocyte chemoattractant protein-1 [MCP-1]). [3][4][5] Infusion of Ang II into hypercholesterolemic mice dramatically accelerates the atherosclerotic process, leading to the development of extensive atherosclerotic plaque formation and abdominal aortic aneurysm (AAA). 6,7 The Ang II-mediated acceleration of atherogenesis is characterized by the recruitment and activation of monocytes/macrophages and the degradation of elastin and collagen layers, suggesting that Ang II changes the lesion composition into a more destabilized phenotype. MCP-1 is a C-C chemokine that controls monocyte recruitment to the site of inflammation through its receptor, C-C chemokine receptor (CCR) 2. 8 -10 We recently demonstrated that blockade of the MCP-1 pathway by transfection of mutant MCP-1 gene limits Ang II-induced progression and destabilization of atherosclerotic 20 It is imposs...

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