From the Department of Medicine, University of Washington School of Medicine, Seattle.
Arterioscler Thromb Vasc Biol. 2018 Jan;38(1):206-217. doi: 10.1161/ATVBAHA.117.309565. Epub 2017 Nov 9.
Gene therapy that expresses apo A-I (apolipoprotein A-I) from vascular wall cells has promise for preventing and reversing atherosclerosis. Previously, we reported that transduction of carotid artery endothelial cells with a helper-dependent adenoviral (HDAd) vector expressing apo A-I reduced early (4 weeks) fatty streak development in fat-fed rabbits. Here, we tested whether the same HDAd could provide long-term protection against development of more complex lesions.
Fat-fed rabbits (n=25) underwent bilateral carotid artery gene transfer, with their left and right common carotids randomized to receive either a control vector (HDAdNull) or an apo A-I-expressing vector (HDAdApoAI). Twenty-four additional weeks of high-fat diet yielded complex intimal lesions containing lipid-rich macrophages as well as smooth muscle cells, often in a lesion cap. Twenty-four weeks after gene transfer, high levels of apo A-I mRNA (median ≥250-fold above background) were present in all HDAdApoAI-treated arteries. Compared with paired control HDAdNull-treated arteries in the same rabbit, HDAdApoAI-treated arteries had 30% less median intimal lesion volume (=0.03), with concomitant reductions (23%-32%) in intimal lipid, macrophage, and smooth muscle cell content (≤0.05 for all). HDAdApoAI-treated arteries also had decreased intimal inflammatory markers. VCAM-1 (vascular cell adhesion molecule-1)-stained area was reduced by 36% (=0.03), with trends toward lower expression of ICAM-1 (intercellular adhesion molecule-1), MCP-1 (monocyte chemoattractant protein 1), and TNF-α (tumor necrosis factor-α; 13%-39% less; =0.06-0.1).
In rabbits with severe hyperlipidemia, transduction of vascular endothelial cells with an apo A-I-expressing HDAd yields at least 24 weeks of local apo A-I expression that durably reduces atherosclerotic lesion growth and intimal inflammation.
从血管壁细胞表达载脂蛋白 A-I（apo A-I）的基因治疗有望预防和逆转动脉粥样硬化。以前，我们报道过，用辅助依赖性腺病毒（HDAd）载体转导颈动脉内皮细胞表达 apo A-I 可减少高脂肪饮食喂养的兔子早期（4 周）脂肪条纹的发展。在这里，我们测试了相同的 HDAd 是否可以提供长期保护，防止更复杂病变的发展。
给 25 只高脂肪饮食喂养的兔子进行双侧颈动脉基因转移，其左右颈总动脉随机接受对照载体（HDAdNull）或载脂蛋白 A-I 表达载体（HDAdApoAI）。24 周的高脂饮食导致含有富含脂质的巨噬细胞和平滑肌细胞的复杂内膜病变，通常在病变帽中。基因转移后 24 周，所有接受 HDAdApoAI 治疗的动脉中都存在高水平的 apo A-I mRNA（中位数比背景高 250 倍以上）。与同一只兔子中配对的对照 HDAdNull 治疗的动脉相比，HDAdApoAI 治疗的动脉内膜病变体积中位数减少 30%（=0.03），内膜脂质、巨噬细胞和平滑肌细胞含量减少（所有均减少 23%-32%）（≤0.05）。HDAdApoAI 治疗的动脉内膜炎症标志物也减少。VCAM-1（血管细胞黏附分子-1）染色面积减少 36%（=0.03），ICAM-1（细胞间黏附分子-1）、MCP-1（单核细胞趋化蛋白 1）和 TNF-α（肿瘤坏死因子-α）的表达呈下降趋势（分别减少 13%-39%，=0.06-0.1）。
在严重高脂血症的兔子中，用载脂蛋白 A-I 表达的 HDAd 转导血管内皮细胞可产生至少 24 周的局部 apo A-I 表达，持久地减少动脉粥样硬化病变的生长和内膜炎症。
