title: Angiotensin-converting enzyme inhibition down-regulates the pro-atherogenic chemokine receptor 9 (CCR9)-chemokine ligand 25 (CCL25) axis.
abstract: Many experimental and clinical studies suggest a relationship between enhanced angiotensin II release by the angiotensin-converting enzyme (ACE) and the pathophysiology of atherosclerosis. The atherosclerosis-enhancing effects of angiotensin II are complex and incompletely understood. To identify anti-atherogenic 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.
authors.affiliation: Molecular Pharmacology Unit, Swiss Federal Institute of Technology and University of Zurich, CH-8057 Zurich, Switzerland.
authors.forename: Joshua
authors.initials: J
authors.lastname: Abd Alla
authors.forename: Andreas
authors.initials: A
authors.lastname: Langer
authors.forename: Sherif S
authors.initials: SS
authors.lastname: Elzahwy
authors.forename: Gökhan
authors.initials: G
authors.lastname: Arman-Kalcek
authors.forename: Thomas
authors.initials: T
authors.lastname: Streichert
authors.forename: Ursula
authors.initials: U
authors.lastname: Quitterer
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D002216:Captopril / Q000494:pharmacology; D019742:Chemokines, CC / Q000235:genetics* / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003324:Coronary Artery Disease / Q000150:complications; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D054388:Receptors, CCR / Q000235:genetics* / Q000378:metabolism; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001057:Apolipoproteins E; C119309:CC chemokine receptor 9; C108074:CCL25 protein, human; D019742:Chemokines, CC; D044140:Receptor, Angiotensin, Type 1; D054388:Receptors, CCR; D002784:Cholesterol; D002216:Captopril; D007703:Peptidyl-Dipeptidase A