P53 Gene Therapy Modulates Signal Transduction in the Apoptotic and Cell Cycle Pathways Downregulating Neointimal Hyperplasia
P53 Gene Therapy Modulates Signal Transduction in the Apoptotic and Cell Cycle Pathways Downregulating Neointimal Hyperplasia
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DOI：
10.1177/1538574411422277
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发表时间：
2012-01-01
影响因子：
0.9
通讯作者：
Ascher, Enrico
中科院分区：
文献类型：
--
作者：
Jacob, Theresa;Hingorani, Anil;Ascher, Enrico
目的：探讨p53基因治疗抑制血管内膜增生（IH）的分子机制。方法：利用腺病毒载体将p53基因转移到球囊损伤的大鼠颈动脉中。免疫组化检测p53、p21、Rb、Bcl-2、Bax和Bcl-x的表达。检测细胞周期蛋白D Ⅰ、Fas/CD95和聚ADP核糖聚合酶（PARP）的表达。结果如下：我们的数据表明，与对照组相比，培养基中血管平滑肌细胞（VSMCs）核中p53的表达增加（P <0.01）。在治疗的动物中，Bax和Bcl-x、p21和Rb显著上调（P <0.01）。Bcl-2的免疫反应仅在14天未处理组的新生内膜中观察到。在p53处理的动物的VSMCs的细胞质中观察到Fas的存在增加和PARP的表达减少。结论：P53基因转移激活了一系列下游效应基因，其产物直接参与细胞周期阻滞、DNA修复和凋亡。
Purpose: To investigate the molecular mechanisms that lead to inhibition of intimal hyperplasia (IH) following p53 gene therapy. Methods: In vivo p53 gene transfer to balloon injured rat carotid arteries was performed by utilizing adenovirus. The relationship between p53, p21, retinoblastoma protein (Rb), B-cell lymphoma 2 (Bcl-2), Bax, and Bcl-x was examined by immunohistochemistry. Expression of cyclin D I, Fas/CD95, and poly(ADP-ribose)polymerase (PARP) was determined. Results: Our data indicate increased expression of p53 in the nuclei of vascular smooth muscle cells (VSMCs) in the media (P < .01) compared with the controls. In the treated animals, Bax and Bcl-x, p21, and Rb were significantly upregulated (P < .01). lmmunoreactivity to Bcl-2 was observed only in the neointima of untreated groups at 14 days. An increased presence of Fas and decreased expression of PARP was observed in the cytoplasm of the VSMCs of p53-treated animals. Conclusions: P53 gene transfer activated a battery of downstream effector genes whose products are directly involved in cell cycle arrest, DNA repair, and apoptosis.