期刊
CIRCULATION
卷 107, 期 21, 页码 2726-2732出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.CIR.0000066913.69844.B2
关键词
gene therapy; apolipoproteins; hypercholesterolemia; atherosclerosis; adenovirus
Background - Epidemiologic studies and transgenic mouse experiments indicate that high plasma HDL and apolipoprotein (apo) A-I protect against atherosclerosis. We used helper-dependent adenovirus (HD-Ad) gene transfer to examine the effect of long-term hepatic apoA-I expression on atherosclerotic lesion progression and remodeling in a mouse model of familial hypercholesterolemia. Methods and Results - We treated LDL receptor - deficient ( LDLR -/-) mice maintained on a high-cholesterol diet for 6 weeks with either a HD-Ad containing human apoA-I gene (HD-Ad-AI) or saline ( control). HD-Ad-AI treatment did not affect plasma liver enzymes but induced the appearance of plasma human apoA-I at or above human levels for the duration of the study. Substantial amounts of human apoA-I existed in lipid-free plasma. Compared with controls, HDLs from treated mice were larger and had a greater inhibitory effect on tumor necrosis factor-alpha-induced vascular cellular adhesion molecule-1 expression in cultured endothelial cells. Twenty-four weeks after injection, aortic atherosclerotic lesion area in saline-treated mice progressed approximate to700%; the rate of progression was reduced by >50% by HD-Ad-AI treatment. The lesions in HD-Ad-AI - treated mice contained human apoA-I that colocalized mainly with macrophages; they also contained less lipid, fewer macrophages, and less vascular cellular adhesion molecule-1 immunostaining but more smooth muscle cells (alpha-actin staining) and collagen. Conclusions - HD- Ad-AI treatment of LDLR-/- mice leads to long-term overexpression of apoA-I, retards atherosclerosis progression, and remodels the lesions to a more stable-appearing phenotype. HD- Ad - mediated transfer of apoA-I may be a useful clinical approach for protecting against atherosclerosis progression and stabilizing atherosclerotic lesions associated with dyslipidemia in human patients.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据