title: Enalapril attenuates angiotensin II-induced atherosclerosis and vascular inflammation.
abstract: Angiotensin converting enzyme (ACE) inhibitors prevent a wide variety of key events underlying atherogenesis. Whether these actions depend solely on reduction of angiotensin II (Ang II) generation is still to be determined. This study was undertaken to determine whether enalapril, an ACE inhibitor, prevents atherosclerosis and vascular inflammation induced by Ang II in apolipoprotein E-deficient (apoE-KO) mice. Subcutaneous infusion of Ang II (1.44 mg/(kg day)) for 4 weeks increased blood pressure and accelerated atherosclerosis development in the carotid arteries. The expression of the endothelial adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), as well as the chemokines monocyte chemotactic protein-1 (MCP-1) and macrophage-colony stimulating factor (M-CSF) was up-regulated in the aortas of Ang II-treated mice. Enalapril co-treatment (25 mg/(kg day), in drinking water) prevented the development of atherosclerosis without affecting blood pressure or circulating cholesterol. In addition to preventing the Ang II-induced over-expression of adhesion molecules and chemokines in the aorta, enalapril up-regulated the expression of peroxisome proliferator-activated receptors (PPARs)-alpha and -gamma, potential anti-inflammatory transcription factors. In the aortic arch, a lesion-prone site, the co-treatment with enalapril reduced the percentage of arterial wall occupied by macrophages and foam cells, medial sclerosis and elastin reduplication. Together, these data suggest an important role for Ang II-independent mechanisms in the antiatherogenic and anti-inflammatory effects of ACE inhibitors.
authors.affiliation: Department of Pharmacology, Berlex Biosciences, 2600 Hilltop Drive, PO Box 4099, Richmond, CA 94806, USA. valdeci_da_cunha@berlex.com
authors.forename: Valdeci
authors.initials: V
authors.lastname: da Cunha
authors.forename: Doris M
authors.initials: DM
authors.lastname: Tham
authors.forename: Baby
authors.initials: B
authors.lastname: Martin-McNulty
authors.forename: Gary
authors.initials: G
authors.lastname: Deng
authors.forename: Jerrick J
authors.initials: JJ
authors.lastname: Ho
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Wilson
authors.forename: John C
authors.initials: JC
authors.lastname: Rutledge
authors.forename: Ronald
authors.initials: R
authors.lastname: Vergona
authors.forename: Mark E
authors.initials: ME
authors.lastname: Sullivan
authors.forename: Yi-Xin Jim
authors.initials: YX
authors.lastname: Wang
mesh_terms: D000804:Angiotensin II; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001014:Aortic Aneurysm / Q000139:chemically induced / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency; D001161:Arteriosclerosis / Q000139:chemically induced* / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000235:genetics; D018925:Chemokines / Q000378:metabolism; D004656:Enalapril / Q000494:pharmacology*; D004727:Endothelium / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation; D014657:Vasculitis / Q000139:chemically induced* / Q000473:pathology*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001057:Apolipoproteins E; D015815:Cell Adhesion Molecules; D018925:Chemokines; D047493:PPAR alpha; D047495:PPAR gamma; D012333:RNA, Messenger; D000804:Angiotensin II; D004656:Enalapril