Weighted Gene Co-expression Network Analysis Identifies FKBP11 as a Key Regulator in Acute Aortic Dissection through a NF-kB Dependent Pathway.
Weighted Gene Co-expression Network Analysis Identifies FKBP11 as a Key Regulator in Acute Aortic Dissection through a NF-kB Dependent Pathway.
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加权基因共表达网络分析确定 FKBP11 通过 NF-kB 依赖性途径作为急性主动脉夹层的关键调节因子
DOI：
10.3389/fphys.2017.01010
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发表时间：
2017
影响因子：
4
通讯作者：
Zeng H
中科院分区：
文献类型：
--
作者：
Wang T;He X;Liu X;Liu Y;Zhang W;Huang Q;Liu W;Xiong L;Tan R;Wang H;Zeng H
急性主动脉夹层（AAD）是一种危及生命的疾病。尽管死亡风险较高，但目前还没有有效的治疗方法可以改善AAD的发生或进展。识别AAD的共表达基因或代表性生物标志物的有意义的簇可能有助于识别新的病理机制并促进新疗法的开发。为此，我们进行了加权基因共表达网络分析（WGCNA）和计算模块性状相关性的基础上，一个公共的微阵列数据集（GSE 52093），发现9个模块被发现与AAD。进一步分析与AAD正相关性最强的模块，确定了前10个枢纽基因SLC20A1、GINS 2、CNN1、FAM198B、MAD2L2、UBE2T、FKBP 11、SLMAP、CCDC 34和GALK 1。此外，我们在来自我们研究中心的独立样本集中通过qRT-PCR验证了数据。总体而言，qRT-PCR结果与微阵列分析的结果一致。有趣的是，发现FKBP11的变化最大，FKBP11是一种属于肽基脯氨酰顺式/反式异构酶FKBP家族的蛋白质，其催化含脯氨酸的多肽的折叠。与基因表达分析一致，血管紧张素II处理诱导培养的内皮细胞和夹层主动脉内皮中FKBP11表达。更重要的是，我们发现FKBP11通过与NF-κ B p65亚基相互作用引起内皮细胞的炎症，导致促炎细胞因子的产生。因此，siRNA介导的FKBP11在培养的内皮细胞中的敲低抑制了血管紧张素II诱导的单核细胞通过内皮单层的迁移。基于这些数据，我们假设AAD条件下内皮中FKBP 11过表达引发的促炎细胞因子可以促进循环单核细胞跨内皮迁移到主动脉中，在那里它们分化为活性巨噬细胞并分泌MMPs和其他细胞外基质（ECM）降解蛋白，导致持续的炎症和AAD。总之，我们的数据确定了FKBP11的重要作用，它可以作为AAD的生物标志物和/或治疗靶点。
Acute aortic dissection (AAD) is a life-threatening disease. Despite the higher risk of mortality, currently there are no effective therapies that can ameliorate AAD development or progression. Identification of meaningful clusters of co-expressed genes or representative biomarkers for AAD may help to identify new pathomechanisms and foster development of new therapies. To this end, we performed a weighted gene co-expression network analysis (WGCNA) and calculated module-trait correlations based on a public microarray dataset (GSE 52093) and discovered 9 modules were found to be related to AAD. The module which has the strongest positive correlation with AAD was further analyzed and the top 10 hub genes SLC20A1, GINS2, CNN1, FAM198B, MAD2L2, UBE2T, FKBP11, SLMAP, CCDC34, and GALK1 were identified. Furthermore, we validated the data by qRT-PCR in an independent sample set originated from our study center. Overall, the qRT-PCR results were consistent with the results of the microarray analysis. Intriguingly, the highest change was found for FKBP11, a protein belongs to the FKBP family of peptidyl-prolyl cis/trans isomerases, which catalyze the folding of proline-containing polypeptides. In congruent with the gene expression analysis, FKBP11 expression was induced in cultured endothelial cells by angiotensin II treatment and endothelium of the dissected aorta. More importantly we show that FKBP11 provokes inflammation in endothelial cells by interacting with NF-kB p65 subunit, resulting in pro-inflammatory cytokines production. Accordingly, siRNA mediated knockdown of FKBP11 in cultured endothelial cells suppressed angiotensin II induced monocyte transmigration through the endothelial monolayer. Based on these data, we hypothesize that pro-inflammatory cytokines elicited by FKBP11 overexpression in the endothelium under AAD condition could facilitate transendothelial migration of the circulating monocytes into the aorta, where they differentiate into active macrophages and secrete MMPs and other extracellular matrix (ECM) degrading proteins, contributing to sustained inflammation and AAD. Taken together, our data identify important role of FKBP11 which can serve as biomarker and/or therapeutic target for AAD.
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影响因子：
4.8
作者：
Erlejman, Alejandra G.;De Leo, Sonia A.;Galigniana, Mario D.
通讯作者：
Galigniana, Mario D.
影响因子：
3.5
作者：
Liu R;Jin JP
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WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
影响因子：
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作者：
Ohtani, K;Egashira, K;Sunagawa, K
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Sunagawa, K
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作者：
Liu J;Li Y;Liu L;Wang Z;Shi C;Cheng Z;Zhang X;Ding F;Chen PS
通讯作者：
Chen PS