Temporal network based analysis of cell specific vein graft transcriptome defines key pathways and hub genes in implantation injury.
Temporal network based analysis of cell specific vein graft transcriptome defines key pathways and hub genes in implantation injury.
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DOI：
10.1371/journal.pone.0039123
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
LoGerfo FW
中科院分区：
文献类型：
--
作者：
Bhasin M;Huang Z;Pradhan-Nabzdyk L;Malek JY;LoGerfo PJ;Contreras M;Guthrie P;Csizmadia E;Andersen N;Kocher O;Ferran C;LoGerfo FW
静脉移植失败发生在植入后1 - 6个月，原因是梗阻性内膜增生，部分与植入损伤有关。在手术后2小时(H)至30天(D)，通过激光捕获犬静脉移植物的微解剖内皮细胞（EC）和内侧平滑肌细胞（SMC）的转录谱分析，确定了转录组对静脉移植物植入损伤的细胞特异性和时间反应。我们的研究结果表明，植入损伤在2 H时开始，在12-24 H时达到峰值，在7 D时下降，在30 D时消退。差异表达基因的基因本体和途径分析表明，植入损伤影响两种细胞类型的炎症和免疫反应、凋亡、有丝分裂和细胞外基质重组。通过反向传播，构建了一个完整的网络，从30 D时的差异表达基因开始，然后加入每个先前时间点的上游交互基因。在移植物EC和SMC中，IL-6、IL-8、NF-κB、树突状细胞成熟、糖皮质激素受体和髓系细胞触发受体（TREM-1）信号通路以及PPARα激活途径显著富集。基于交互式网络的分析发现，IL-6、IL-8、IL-1α和胰岛素受体（INSR）是这些通路中的焦点中心基因。Real-time PCR用于验证其中两个基因：IL-6和IL-8，以及胶原11A1 (COL11A1)，这是反向繁殖的基石。总之，这些结果建立了因果关系，阐明了静脉移植损伤的发病机制，并确定了预防静脉移植损伤的新靶点。
Vein graft failure occurs between 1 and 6 months after implantation due to obstructive intimal hyperplasia, related in part to implantation injury. The cell-specific and temporal response of the transcriptome to vein graft implantation injury was determined by transcriptional profiling of laser capture microdissected endothelial cells (EC) and medial smooth muscle cells (SMC) from canine vein grafts, 2 hours (H) to 30 days (D) following surgery. Our results demonstrate a robust genomic response beginning at 2 H, peaking at 12–24 H, declining by 7 D, and resolving by 30 D. Gene ontology and pathway analyses of differentially expressed genes indicated that implantation injury affects inflammatory and immune responses, apoptosis, mitosis, and extracellular matrix reorganization in both cell types. Through backpropagation an integrated network was built, starting with genes differentially expressed at 30 D, followed by adding upstream interactive genes from each prior time-point. This identified significant enrichment of IL-6, IL-8, NF-κB, dendritic cell maturation, glucocorticoid receptor, and Triggering Receptor Expressed on Myeloid Cells (TREM-1) signaling, as well as PPARα activation pathways in graft EC and SMC. Interactive network-based analyses identified IL-6, IL-8, IL-1α, and Insulin Receptor (INSR) as focus hub genes within these pathways. Real-time PCR was used for the validation of two of these genes: IL-6 and IL-8, in addition to Collagen 11A1 (COL11A1), a cornerstone of the backpropagation. In conclusion, these results establish causality relationships clarifying the pathogenesis of vein graft implantation injury, and identifying novel targets for its prevention.
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影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
DOI：
10.1016/j.jamcollsurg.2006.12.029
发表时间：
2007-03-01
影响因子：
5.2
作者：
Andersen, Nicholas D.;Monahan, Thomas S.;LoGerfo, Frank W.
通讯作者：
LoGerfo, Frank W.
影响因子：
4.3
作者：
Kalish, JA;Willis, DJ;Logerfo, FW
通讯作者：
Logerfo, FW
影响因子：
14.9
作者：
Huang DW;Sherman BT;Tan Q;Kir J;Liu D;Bryant D;Guo Y;Stephens R;Baseler MW;Lane HC;Lempicki RA
通讯作者：
Lempicki RA
影响因子：
0.9
作者：
He, X. P.;Li, X. X.;Gu, X. H.
通讯作者：
Gu, X. H.