Many experimental and clinical studies suggest a relationship between enhanced angiotensin II release by the angiotensinconverting enzyme (ACE) and the pathophysiology of atherosclerosis. The atherosclerosis-enhancing effects of angiotensin II are complex and incompletely understood. To identify antiatherogenic target genes, we performed microarray gene expression profiling of the aorta during atherosclerosis prevention with the ACE inhibitor, captopril. Atherosclerosis-prone apolipoprotein E (apoE)-deficient mice were used as a model to decipher susceptible genes regulated during atherosclerosis prevention with captopril. Microarray gene expression profiling and immunohistology revealed that captopril treatment for 7 months strongly decreased the recruitment of pro-atherogenic immune cells into the aorta. Captopril-mediated inhibition of plaque-infiltrating immune cells involved down-regulation of the C-C chemokine receptor 9 (CCR9). Reduced cell migration correlated with decreased numbers of aorta-resident cells expressing the CCR9-specific chemoattractant factor, chemokine ligand 25 (CCL25). The CCL25-CCR9 axis was pro-atherogenic, because inhibition of CCR9 by RNA interference in hematopoietic progenitors of apoE-deficient mice significantly retarded the development of atherosclerosis. Analysis of coronary artery biopsy specimens of patients with coronary artery atherosclerosis undergoing bypass surgery also showed strong infiltrates of CCR9-positive cells in atherosclerotic lesions. Thus, the C-C chemokine receptor, CCR9, exerts a significant role in atherosclerosis.Several clinical studies show that pharmacological inhibition of the renin-angiotensin-aldosterone system could mediate atheroprotection (1-4). In agreement with those clinical data, experimental studies demonstrated a causal relationship between angiotensin II release by the angiotensin-converting enzyme (ACE), 2 the angiotensin II AT 1 receptor, and the development of atherosclerosis because genetic inactivation of either ACE or the AT 1 receptor prevents atherosclerosis development in various animal models of atherosclerosis (5, 6). Likewise, inhibition of angiotensin II activity by ACE inhibitors or AT 1 receptor antagonists is curative in such animal models of atherosclerosis (7,8).In view of the major anti-atherosclerotic effects of ACE inhibitors and AT 1 antagonists, many studies investigated mechanisms that could contribute to atheroprotection upon angiotensin II inhibition. The effects of angiotensin II in atherosclerosis are complex involving actions on circulating blood cells and arterial smooth muscle cells as major targets (9 -11). Established pro-atherogenic effects of angiotensin II on smooth muscle cells are related to a phenotype transformation from contractile to synthetic (11). The effects of angiotensin II on circulating immune cells are less clear, although, gene inactivation studies clearly demonstrated the involvement of circulating blood and progenitor cells in the atherosclerosis-enhancing activity of ACE and the AT 1 r...