Coronary artery endothelial transcriptome in vivo: identification of endoplasmic reticulum stress and enhanced reactive oxygen species by gene connectivity network analysis.
Coronary artery endothelial transcriptome in vivo: identification of endoplasmic reticulum stress and enhanced reactive oxygen species by gene connectivity network analysis.
复制标题
DOI：
10.1161/circgenetics.110.958926
复制
发表时间：
2011-06
期刊：
影响因子：
--
通讯作者：
Davies PF
中科院分区：
文献类型：
--
作者：
Civelek M;Manduchi E;Riley RJ;Stoeckert CJ Jr;Davies PF
内皮功能对于动脉粥样硬化的定位至关重要。解决了动脉床特性和位点特异性动脉粥样硬化易感性的体内内皮表型足迹。从 76 头正常猪中分离出来自 13 个对动脉粥样硬化具有不同易感性的离散冠状动脉和非冠状动脉区域的 98 个内皮细胞样本。分析转录谱以确定体内内皮表型的稳态。利用加权基因共表达网络的无监督系统生物学方法确定了高度相关的内皮基因。连接网络分析确定了 19 个基因模块，其中 12 个显示与循环床分类显着相关。冠状动脉和非冠状动脉内皮之间 1,300 个基因的差异表达表明，不同的冠状动脉内皮表型具有最高的显着性，这些表型富含与内质网 (ER) 应激和未折叠蛋白结合、转录和翻译调节以及氧化还原稳态相关的生物功能。此外，在冠状动脉内，易感近端区域与受保护远端区域的内皮转录谱的比较表明易感部位存在内质网应激条件。整个冠状动脉内皮的活性氧 (ROS) 积累量高于非冠状动脉内皮，这与冠状动脉 ER 应激和冠状动脉中抗氧化基因的内皮表达较低一致。基因连接分析区分了冠状动脉和非冠状动脉内皮转录谱，并确定了与冠状动脉 ER 和氧化应激增加相关的差异转录水平，这与动脉粥样硬化易感性增强一致。
Endothelial function is central to the localization of atherosclerosis. The in vivo endothelial phenotypic footprints of arterial bed identity and site-specific athero-susceptibility are addressed. 98 endothelial cell samples from 13 discrete coronary and non-coronary arterial regions of varying susceptibilities to atherosclerosis were isolated from 76 normal swine. Transcript profiles were analyzed to determine the steady state in vivo endothelial phenotypes. An unsupervised systems biology approach utilizing weighted gene co-expression networks determined highly correlated endothelial genes. Connectivity network analysis identified 19 gene modules, 12 of which showed significant association with circulatory bed classification. Differential expression of 1,300 genes between coronary and non-coronary artery endothelium suggested distinct coronary endothelial phenotypes with highest significance expressed in gene modules enriched for biological functions related to endoplasmic reticulum (ER) stress and unfolded protein binding, regulation of transcription and translation, and redox homeostasis. Furthermore, within coronary arteries comparison of endothelial transcript profiles of susceptible proximal regions to protected distal regions suggested the presence of ER stress conditions in susceptible sites. Accumulation of reactive oxygen species (ROS) throughout coronary endothelium was greater than in non-coronary endothelium consistent with coronary artery ER stress and the lower endothelial expression of anti-oxidant genes in coronary arteries. Gene connectivity analyses discriminated between coronary and non-coronary endothelial transcript profiles and identified differential transcript levels associated with increased ER and oxidative stress in coronary arteries, consistent with enhanced susceptibility to atherosclerosis.