Department of Medicine, University of Washington, Seattle, Washington 98195-7710, USA.
Mol Ther. 2011 Oct;19(10):1833-41. doi: 10.1038/mt.2011.133. Epub 2011 Jul 19.
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.
在血管壁中表达抗动脉粥样硬化基因可能是预防或逆转动脉粥样硬化的有效方法。这种方法的发展受到缺乏合适的基因转移载体的阻碍。我们使用辅助依赖性腺病毒（HDAd）载体来测试在动脉壁中表达载脂蛋白 A-I（apoA-I）是否可以延缓高脂血症兔动脉粥样硬化的发展。用表达兔 apoA-I 的 HDAd 或“空”HDAd 灌注颈总动脉，2 周和 4 周后收获。仅在 HDAdApoAI 动脉中检测到 apoA-I mRNA 和蛋白。在 2 周时，两组的病变大小、脂质和巨噬细胞含量以及粘附分子表达相似。在 2 周至 4 周之间，HDAdNull 动脉中大多数这些动脉粥样硬化指标增加，但在 HDAdApoAI 动脉中稳定或减少（所有终点在 4 周 HDAdApoAI 与 HDAdNull 动脉之间的 P ≤ 0.04）。在食素兔中的一项长期研究表明，HDAd 载体 DNA 和 apoA-I 表达至少持续 48 周，载体 DNA 含量和 apoA-I 表达从 4 周到 48 周稳定。动脉内皮中 apoA-I 的表达显著延缓动脉粥样硬化。HDAd 为动脉壁中的治疗性转基因提供了长期、稳定的表达。
