Apolipoprotein A-I vascular gene therapy reduces vein-graft atherosclerosis.
Apolipoprotein A-I vascular gene therapy reduces vein-graft atherosclerosis.
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DOI：
10.1016/j.omtm.2023.08.018
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发表时间：
2023-09-14
期刊：
影响因子：
--
通讯作者：
Dichek, David A.
中科院分区：
文献类型：
--
作者：
Bi, Lianxiang;Wacker, Bradley K.;Komandur, Kaushik;Sanford, Nicole;Dichek, David A.
冠状动脉静脉旁路移植术通常失败，因为动脉粥样硬化驱动的脂质和巨噬细胞积累。静脉移植物动脉粥样硬化的治疗仅限于他汀类药物，这些药物的疗效有限。我们假设，用表达载脂蛋白AI的辅助依赖性腺病毒（HDAdApoAI）转导脂肪喂养的兔的静脉移植物内皮细胞将减少脂质和巨噬细胞的积聚。采用双侧颈外静脉-颈动脉间置移植术。四周后，每只兔（n = 23只兔）的一个移植物输注HDAdApoAI，对侧移植物输注HDAdApoAI。12周后收获移植物。对移植物进行配对分析，以静脉移植物胆固醇、内膜脂质和巨噬细胞含量作为主要终点。所有移植物中均检测到HDAd基因组。HDAdApoAI移植物中APOAI mRNA的中位数比HDAdhesive移植物高63倍（p < 0.001）。HDAdApoAI移植物的总胆固醇平均降低15%（通过质谱法; p = 0.003）;内膜脂质平均降低19%（通过油红O染色; p = 0.02）;巨噬细胞标志物CD 68的表达平均降低13%（通过逆转录酶介导的定量PCR; p = 0.008）。静脉移植物内皮的体内转导实现了持续的APOAI表达，并降低了静脉移植物胆固醇、内膜脂质和CD 68表达。APOAI的血管基因治疗有望预防动脉粥样硬化引起的静脉移植失败。HDAdApoAI在高脂血症兔静脉移植物中降低胆固醇和内膜脂质积聚。由于静脉移植物动脉粥样硬化及其并发症（包括斑块破裂导致闭塞）是由脂质积累驱动的，因此这种基因治疗有可能增加长期静脉移植物通畅性。
Coronary artery venous bypass grafts typically fail because of atherosclerosis driven by lipid and macrophage accumulation. Therapy for vein-graft atherosclerosis is limited to statin drugs, which are only modestly effective. We hypothesized that transduction of vein-graft endothelium of fat-fed rabbits with a helper-dependent adenovirus expressing apolipoprotein AI (HDAdApoAI) would reduce lipid and macrophage accumulation. Fat-fed rabbits received bilateral external jugular vein-to-carotid artery interposition grafts. Four weeks later, one graft per rabbit (n = 23 rabbits) was infused with HDAdApoAI and the contralateral graft with HDAdNull. Grafts were harvested 12 weeks later. Paired analyses of grafts were performed, with vein graft cholesterol, intimal lipid, and macrophage content as the primary endpoints. HDAd genomes were detected in all grafts. APOAI mRNA was median 63-fold higher in HDAdApoAI grafts versus HDAdNull grafts (p < 0.001). HDAdApoAI grafts had a mean 15% lower total cholesterol (by mass spectrometry; p = 0.003); mean 19% lower intimal lipid (by oil red O staining; p = 0.02); and mean 13% lower expression of the macrophage marker CD68 (by reverse transcriptase-mediated quantitative PCR; p = 0.008). In vivo transduction of vein-graft endothelium achieves persistent APOAI expression and reduces vein-graft cholesterol, intimal lipid, and CD68 expression. Vascular gene therapy with APOAI has promise for preventing vein-graft failure caused by atherosclerosis. HDAdApoAI in vein grafts of hyperlipidemic rabbits decreased cholesterol and intimal lipid accumulation. Because vein graft atherosclerosis and its complications (including plaque rupture leading to occlusion) are driven by lipid accumulation, this gene therapy has the potential to increase long-term vein graft patency.
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影响因子：
64.5
作者：
Bjoerkegren, Johan L. M.;Lusis, Aldons J.
通讯作者：
Lusis, Aldons J.
影响因子：
9.3
作者：
Audisio, Katia;Halbreiner, M. Scott;Gaudino, Mario
通讯作者：
Gaudino, Mario
影响因子：
5.3
作者：
Andreeva, ER;Pugach, IM;Orekhov, AN
通讯作者：
Orekhov, AN
影响因子：
37.8
作者：
Bandaru, Sashidar;Ala, Chandu;Akyiirek, Levent M.
通讯作者：
Akyiirek, Levent M.
DOI：
10.1016/0735-1097(96)00206-9
发表时间：
1996-09-01
影响因子：
24
作者：
FitzGibbon, GM;Kafka, HP;Burton, JR
通讯作者：
Burton, JR