Prevention of neointimal formation using miRNA-126-containing nanoparticle-conjugated stents in a rabbit model.
Prevention of neointimal formation using miRNA-126-containing nanoparticle-conjugated stents in a rabbit model.
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DOI：
10.1371/journal.pone.0172798
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Ono K
中科院分区：
文献类型：
--
作者：
Izuhara M;Kuwabara Y;Saito N;Yamamoto E;Hakuno D;Nakashima Y;Horie T;Baba O;Nishiga M;Nakao T;Nishino T;Nakazeki F;Ide Y;Kimura M;Kimura T;Ono K
尽管药物洗脱支架最近取得了进展，但血管内介入治疗后的再狭窄和血栓形成仍然是心血管疾病治疗的主要限制。这些问题可能是由于对支架表面新生内膜形成的不适当抑制和再内皮化的延迟引起的。miR-126已被证明具有增强血管内皮细胞增殖的潜力。我们设计并构建了与胆固醇偶联的27-nt双链RNA (dsRNA)，具有高膜透性，转染后形成成熟的miR-126。为了特异位点诱导miR-126，我们使用了聚（dl -丙交酯-共糖醇）纳米颗粒（NPs）。含有miR-126- dsrna的NPs （miR-126 NPs）显著降低了先前鉴定的miR-126靶点SPRED1在人脐血管内皮细胞（HUVECs）中的蛋白表达，miR-126 NPs增强了HUVECs的增殖和迁移。另一方面，miR-126 NPs通过抑制IRS-1减少血管平滑肌细胞的增殖和迁移。最后，我们开发了一种洗脱miR-126的支架系统。该递送系统在兔再狭窄模型中表现出明显的内膜形成抑制作用。miR-126 np -缀合支架显著抑制家兔新生内膜增生的发生。本研究可能为预防血管成形术后再狭窄提供一种新的治疗选择。
Despite recent progress with drug-eluting stents, restenosis and thrombosis after endovascular intervention are still major limitations in the treatment of cardiovascular diseases. These problems are possibly caused by inappropriate inhibition of neointimal formation and retardation of re-endothelialization on the surface of the stents. miR-126 has been shown to have the potential to enhance vascular endothelial cell proliferation. We designed and constructed a 27-nt double strand RNA (dsRNA) conjugated to cholesterol, which has high membrane permeability, and formed mature miR-126 after transfection. For site-specific induction of miR-126, we utilized poly (DL-lactide-co-glycolide) nanoparticles (NPs). miR-126-dsRNA-containing NPs (miR-126 NPs) significantly reduced the protein expression of a previously identified miR-126 target, SPRED1, in human umbilical vascular endothelial cells (HUVECs), and miR-126 NPs enhanced the proliferation and migration of HUVECs. On the other hand, miR-126 NPs reduced the proliferation and migration of vascular smooth muscle cells, via the suppression of IRS-1. Finally, we developed a stent system that eluted miR-126. This delivery system exhibited significant inhibition of neointimal formation in a rabbit model of restenosis. miR-126 NP-conjugated stents significantly inhibited the development of neointimal hyperplasia in rabbits. The present study may indicate the possibility of a novel therapeutic option to prevent restenosis after angioplasty.