title: Expression of apolipoprotein A-I in rabbit carotid endothelium protects against atherosclerosis.
abstract: Expression of atheroprotective genes in the blood vessel wall is potentially an effective means of preventing or reversing atherosclerosis. Development of this approach has been hampered by lack of a suitable gene-transfer vector. We used a helper-dependent adenoviral (HDAd) vector to test whether expression of apolipoprotein A-I (apoA-I) in the artery wall could retard the development of atherosclerosis in hyperlipidemic rabbits. Carotid arteries were infused with an HDAd expressing rabbit apoA-I or a "null" HDAd and harvested 2 and 4 weeks later. ApoA-I mRNA and protein were detected only in HDAdApoAI arteries. Lesion size, lipid and macrophage content, and adhesion molecule expression were similar in both groups at 2 weeks. Between 2 and 4 weeks, most of these measures of atherosclerosis increased in HDAdNull arteries, but were stable or decreased in HDAdApoAI arteries (P ≤ 0.04 for all end points in 4-week HDAdApoAI versus HDAdNull arteries). A longer-term study in chow-fed rabbits revealed persistence of HDAd vector DNA and apoA-I expression for ≥48 weeks, with stable vector DNA content and apoA-I expression from 4 to 48 weeks. Expression of apoA-I in arterial endothelium significantly retards atherosclerosis. HDAd provides prolonged, stable expression of a therapeutic transgene in the artery wall.
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington 98195-7710, USA.
authors.forename: Rowan
authors.initials: R
authors.lastname: Flynn
authors.forename: Kun
authors.initials: K
authors.lastname: Qian
authors.forename: Chongren
authors.initials: C
authors.lastname: Tang
authors.forename: Nagadhara
authors.initials: N
authors.lastname: Dronadula
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Buckler
authors.forename: Bo
authors.initials: B
authors.lastname: Jiang
authors.forename: Shan
authors.initials: S
authors.lastname: Wen
authors.forename: Helén L
authors.initials: HL
authors.lastname: Dichek
authors.forename: David A
authors.initials: DA
authors.lastname: Dichek
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000517:prevention & control*; D002339:Carotid Arteries / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D011817:Rabbits; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology
chemical_list: D016632:Apolipoprotein A-I; D012333:RNA, Messenger; D002784:Cholesterol