Inhibition of vein graft stenosis with a c-jun targeting DNAzyme in a cationic liposomal formulation containing 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)
Inhibition of vein graft stenosis with a c-jun targeting DNAzyme in a cationic liposomal formulation containing 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)
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DOI：
10.1016/j.ijcard.2013.05.092
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发表时间：
2013-10-09
影响因子：
3.5
通讯作者：
Khachigian, Levon M.
中科院分区：
文献类型：
--
作者：
Li, Yue;Bhindi, Ravinay;Khachigian, Levon M.
背景/目的：冠状动脉旁路移植术（CABG）是最常见的心脏外科手术之一。由于狭窄引起的隐静脉移植失败阻碍了CABG的长期成功。静脉移植物狭窄过程中的关键细胞事件是平滑肌细胞增生。在这项研究中，我们评估了靶向转录因子c-Jun的DNAzyme（Dz 13）在含有1，2-二油酰基-3-三甲基铵丙烷（DOTAP）/1，2-二油酰基-sn-甘油基-3-磷酸乙醇胺（DOPE）的阳离子脂质体制剂中在兔静脉移植物狭窄模型中的作用。Dz 13在DOTAP/DOPE已经经历了临床前毒理学测试，和I期临床试验，我们最近进行的基底细胞癌癌症患者表明，它是安全的，耐受性良好的局部administration.Methods后：Dz 13在一个配方中含有DOTAP/DOPE对平滑肌细胞（SMC）的生长和c-Jun表达的影响进行了评估。Dz 13转染通过细胞摄取羧基荧光素标记的Dz 13来确定。结果：Dz 13/DOTAP/DOPE能抑制SMC增殖，抑制c-Jun蛋白表达，与Dz 13催化结构域点突变（Dz 13.G> C）相比，Dz 13/DOTAP/DOPE能抑制SMC增殖，抑制c-Jun蛋白表达。Dz 13（500 μ g）/DOTAP/DOPE形成脂质复合物，其在冰上（0 ℃）胶体稳定长达1小时，在37 ℃胶体稳定30分钟，允许静脉充分吸收。Dz 13（500 μ g）抑制新生内膜形成28天后，端侧transplantation.Conclusions：此配方适用于静脉移植前可能是有用的努力，以减少移植失败。(C)2013爱思唯尔爱尔兰有限公司版权所有。
Background/objectives: Coronary artery bypass grafting(CABG) is among the most commonly performed heart surgical procedures. Saphenous vein graft failure due to stenosis impedes the longer-term success of CABG. A key cellular event in the process of vein graft stenosis is smooth muscle cell hyperplasia. In this study, we evaluated the effect of a DNAzyme(Dz13) targeting the transcription factor c-Jun in a rabbitmodel of vein graft stenosis in a cationic liposomal formulation containing 1,2-dioleoyl-3-trimethylammonium propane(DOTAP)/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine(DOPE). Dz13 in DOTAP/DOPE has undergone preclinical toxicological testing, and a Phase I clinical trial we recently conducted in basal cell carcinoma cancer patients demonstrates that it is safe and well tolerated after local administration.Methods: Effects of Dz13 in a formulation containing DOTAP/DOPE on smoothmuscle cell(SMC) growth and c-Jun expression were assessed. Dz13 transfectionwas determined by cellular uptake of carboxyfluorescein-labeled Dz13. Autologous jugular vein to carotid artery transplantation was performed in New ZealandWhite rabbits to investigate the effect of the Dz13 in DOTAP/DOPE formulation on intimal hyperplasia.Results: Dz13/DOTAP/DOPE reduced SMC proliferation and c-Jun protein expression in vitro comparedwith an impotent form of Dz13 bearing a point mutation in its catalytic domain(Dz13.G > C). The Dz13(500 mu g)/DOTAP/DOPE formed lipoplexes that were colloidally stable for up to 1 h on ice(0 degrees C) and 30 min at 37 degrees C, allowing sufficient uptake by the veins. Dz13(500 mu g) inhibited neointima formation 28 d after end-to-side transplantation.Conclusions: This formulation applied to veins prior to transplantation may potentially be useful in efforts to reduce graft failure. (C) 2013 Elsevier Ireland Ltd. All rights reserved.