SERCA2a gene transfer prevents intimal proliferation in an organ culture of human internal mammary artery
SERCA2a gene transfer prevents intimal proliferation in an organ culture of human internal mammary artery
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DOI：
10.1038/gt.2012.50
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发表时间：
2013-04-01
期刊：
影响因子：
5.1
通讯作者：
Hajjar, R. J.
中科院分区：
文献类型：
--
作者：
Lipskaia, L.;Hadri, L.;Hajjar, R. J.
冠状动脉再狭窄是经皮球囊血管成形术的主要并发症，是由血管平滑肌细胞（VSMC）的新内膜增殖引起的。肌浆/内质网钙 ATP 酶 2a 亚型 (SERCA2a) 是收缩性 VSMC 特有的，之前已报道参与控制增殖和迁移的 Ca2+ 信号通路。此外，据报道，SERCA2a 基因转移可抑制体外 VSMC 增殖并防止大鼠颈动脉损伤模型中的新内膜增厚。本研究的目的是使用人左乳内动脉 (hIMA) 内膜增厚的离体模型来评估 SERCA2a 基因转移对于预防支架内再狭窄的潜在治疗意义。在主动脉冠状动脉搭桥手术时获得的左 hIMA 进行球囊扩张，然后用编码人 SERCA2 和绿色荧光蛋白 (GFP) 或对照基因（β-半乳糖苷酶，β-gal）和 GFP 的腺病毒感染 30 分钟。在恒压和灌注的器官培养物中维持14天的球囊损伤的hIMA中观察到内皮下VSMC的增殖和新内膜增厚。 SERCA2a 基因转移可防止血管重塑，并显着（P < 0.01，n = 5）减少受损动脉中的新内膜增厚（内膜/中膜比率为 0.07 +/- 0.01，而β-半乳糖感染的动脉中为 0.40 +/- 0.03）。这些发现可能对病理性支架内再狭窄的治疗具有潜在影响。基因治疗 (2013) 20, 396-406; doi：10.1038/gt.2012.50； 2012 年 7 月 5 日在线发布
Coronary restenosis, a major complication of percutaneous balloon angioplasty, results from neointimal proliferation of vascular smooth muscle cells (VSMCs). The sarco/endoplasmic reticulum calcium ATPase 2a isoform (SERCA2a), specific to contractile VSMCs, has been reported previously to be involved in the control of the Ca2+-signaling pathways governing proliferation and migration. Moreover, SERCA2a gene transfer was reported to inhibit in vitro VSMC proliferation and to prevent neointimal thickening in a rat carotid injury model. The aim of this study was to evaluate the potential therapeutic interest of SERCA2a gene transfer for prevention of in-stent restenosis using a ex vivo model of human left internal mammary artery (hIMA) intimal thickening. Left hIMAs, obtained at the time of aorto-coronary bypass surgeries, were subjected to balloon dilatation followed by infection for 30 min with adenoviruses encoding either human SERCA2 and green fluorescence protein (GFP) or control gene (beta-galactosidase, beta-gal) and GFP. Proliferation of subendothelial VSMCs and neointimal thickening were observed in balloon-injured hIMA maintained 14 days in organ culture under constant pressure and perfusion. SERCA2a gene transfer prevented vascular remodeling and significantly (P < 0.01, n = 5) reduced neointimal thickening in injured arteries (intima/media ratio was 0.07 +/- 0.01 vs 0.40 +/- 0.03 in beta-gal-infected arteries). These findings could have potential implications for treatment of pathological in-stent restenosis. Gene Therapy (2013) 20, 396-406; doi: 10.1038/gt.2012.50; published online 5 July 2012