Identification of inflammatory gene modules based on variations of human endothelial cell responses to oxidized lipids
Identification of inflammatory gene modules based on variations of human endothelial cell responses to oxidized lipids
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DOI：
10.1073/pnas.0605457103
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发表时间：
2006-08-22
影响因子：
11.1
通讯作者：
Lusis, Aldons J.
中科院分区：
文献类型：
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作者：
Gargalovic, Peter S.;Imura, Minori;Lusis, Aldons J.
氧化磷脂被认为通过刺激内皮细胞（EC）产生炎性细胞因子（如IL-8）促进动脉粥样硬化形成。在小鼠模型的研究中，我们先前证明了内皮细胞对氧化脂质的炎症反应的遗传变异对动脉粥样硬化易感性有重要贡献。我们现在表明，类似的变化发生在培养的主动脉内皮细胞来自多个心脏移植供体。这些变化在传代之间稳定保持，因此反映了遗传或表观遗传调节差异。来自12个个体的主动脉EC培养物的表达阵列分析显示，氧化磷脂调节了> 1，000个基因。我们使用所观察到的样本群体中的变异，构建了一个由15个高度连接的基因模块组成的基因共表达网络。我们发现，几个确定的模块显着丰富的已知途径的基因，并确认一个模块丰富的未折叠蛋白反应（UPR）基因使用siRNA和UPR诱导剂衣霉素。在构建的网络的基础上，我们预测，一个未知功能的基因（MGC 4504）存在于UPR模块是UPR转录激活因子ATF 4的目标。我们的数据还表明，IL-8存在于UPR模块中，并在一定程度上受到UPR的调节。我们通过使用siRNA验证这些。总之，我们表明，个体间的变异性可以用来分组基因的途径和预测基因-基因调控关系，从而确定潜在的目标参与常见疾病的易感性，如动脉粥样硬化。
Oxidized phospholipids are thought to promote atherogenesis by stimulating endothelial cells (ECs) to produce inflammatory cytokines, such as IL-8. In studies with mouse models, we previously demonstrated that genetic variation in inflammatory responses of endothelial cells to oxidized lipids contributes importantly to atherosclerosis susceptibility. We now show that similar variations occur in cultured aortic ECs derived from multiple heart transplant donors. These variations were stably maintained between passages and, thus, reflect either genetic or epigenetic regulatory differences. Expression array analysis of aortic EC cultures derived from 12 individuals revealed that > 1,000 genes were regulated by oxidized phospholipids. We have used the observed variations in the sampled population to construct a gene coexpression network comprised of 15 modules of highly connected genes. We show that several identified modules are significantly enriched in genes for known pathways and confirm a module enriched for unfolded protein response (UPR) genes using siRNA and the UPR inducer tunicamycin. On the basis of the constructed network, we predicted that a gene of unknown function (MGC4504) present in the UPR module is a target for UPR transcriptional activator ATF4. Our data also indicate that IL-8 is present in the UPR module and is regulated, in part, by the UPR. We validate these by using siRNA. In conclusion, we show that interindividual variability can be used to group genes into pathways and predict gene-gene regulatory relationships, thus identifying targets potentially involved in susceptibility to common diseases such as atherosclerosis.