Local arterial nanoparticle delivery of siRNA for NOX2 knockdown to prevent restenosis in an atherosclerotic rat model.
Local arterial nanoparticle delivery of siRNA for NOX2 knockdown to prevent restenosis in an atherosclerotic rat model.
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作者：
动脉粥样硬化和动脉介入均诱导氧化应激，氧化应激部分由NADPH氧化酶介导，NADPH氧化酶在新生内膜增生和再狭窄的发展中起关键作用。对于靶向NADPH氧化酶的NOX 2（Cybb）组分以预防再狭窄的siRNA，用病毒载体进行基因转移是有效的，但在人体中引起安全性问题。我们开发了一种新方法，使用基于氨基酸的纳米颗粒HB-OLD 7将靶向NOX 2的siRNA局部递送到动脉壁。在动脉粥样硬化大鼠模型中，在血管成形术后将siRNA-纳米颗粒复合物转移到局部颈动脉壁中。与血管成形术对照相比，siRNA后2周实验动脉壁中Cybb基因表达（通过定量RT-PCR测量）降低> 87%。新生内膜与中膜面积比减少>83%，管腔与整个动脉面积比增加> 89%。重要器官未显示异常，脾脏Cybb基因表达未显示可检测的变化。因此，使用HB-OLD 7纳米颗粒的局部动脉壁基因转移提供了一种有效的非病毒系统，用于以临床适用的方法敲低NADPH氧化酶基因的有效和安全的局部基因转移。局部动脉敲除Cybb基因可显著抑制新生内膜增生，并保护血管腔，而无全身毒性。
Both atherosclerosis and arterial interventions induce oxidative stress mediated in part by NADPH oxidases that play a pivotal role in the development of neointimal hyperplasia and restenosis. For siRNA targeting of the NOX2 (Cybb) component of NADPH oxidase to prevent restenosis, gene transfer with viral vectors is effective, but raises safety issues in humans. We have developed a new approach using the amino-acid-based nanoparticle HB-OLD7 for local delivery of siRNA targeting NOX2 to the arterial wall. siRNA-nanoparticle complexes were transferred into regional carotid artery walls after angioplasty in an atherosclerotic rat model. Compared to angioplasty controls, Cybb gene expression (measured by quantitative RT-PCR) in the experimental arterial wall 2 weeks after siRNA was reduced >87%. The neointima to media area ratio was decreased >83% and lumen to whole artery area ratio was increased >89%. Vital organs showed no abnormalities and splenic Cybb gene expression showed no detectable change. Thus, local arterial wall gene transfer with HB-OLD7 nanoparticles provides an effective, non-viral system for efficient and safe local gene transfer in a clinically applicable approach to knockdown an NADPH oxidase gene. Local arterial knockdown of the Cybb gene significantly inhibited neointimal hyperplasia and preserved the vessel lumen without systemic toxicity.
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影响因子：
7.4
作者：
Csanyi, Gabor;Taylor, W. Robert;Pagano, Patrick J.
通讯作者：
Pagano, Patrick J.
影响因子：
4.8
作者：
Abid, MR;Yano, K;Aird, WC
通讯作者：
Aird, WC
DOI：
10.1161/atvbaha.108.162362
发表时间：
2008-06-01
影响因子：
8.7
作者：
Matsumae, Hironobu;Yoshida, Yoshinori;Tanaka, Makoto
通讯作者：
Tanaka, Makoto
影响因子：
5.3
作者：
Kanellakis, P;Nestel, P;Bobik, A
通讯作者：
Bobik, A
影响因子：
4.3
作者：
Li, JM;Singh, MJ;Nelson, PR
通讯作者：
Nelson, PR