Xu Keman, Shao Ying, Saaoud Fatma, Gillespie Aria, Drummer Charles, Liu Lu, Lu Yifan, Sun Yu, Xi Hang, Tükel Çagla, Pratico Domenico, Qin Xuebin, Sun Jianxin, Choi Eric T, Jiang Xiaohua, Wang Hong, Yang Xiaofeng
Centers of Cardiovascular Research, Inflammation and Lung Research, Philadelphia, PA, United States.
Neural Sciences, Temple University Lewis Katz School of Medicine, Philadelphia, PA, United States.
Front Cardiovasc Med. 2021 Nov 29;8:773473. doi: 10.3389/fcvm.2021.773473. eCollection 2021.
To determine whether pro-inflammatory lipid lysophosphatidylinositols (LPIs) upregulate the expressions of membrane proteins for adhesion/signaling and secretory proteins in human aortic endothelial cell (HAEC) activation, we developed an EC biology knowledge-based transcriptomic formula to profile RNA-Seq data panoramically. We made the following primary findings: first, G protein-coupled receptor 55 (GPR55), the LPI receptor, is expressed in the endothelium of both human and mouse aortas, and is significantly upregulated in hyperlipidemia; second, LPIs upregulate 43 clusters of differentiation (CD) in HAECs, promoting EC activation, innate immune trans-differentiation, and immune/inflammatory responses; 72.1% of LPI-upregulated CDs are not induced in influenza virus-, MERS-CoV virus- and herpes virus-infected human endothelial cells, which hinted the specificity of LPIs in HAEC activation; third, LPIs upregulate six types of 640 secretomic genes (SGs), namely, 216 canonical SGs, 60 caspase-1-gasdermin D (GSDMD) SGs, 117 caspase-4/11-GSDMD SGs, 40 exosome SGs, 179 Human Protein Atlas (HPA)-cytokines, and 28 HPA-chemokines, which make HAECs a large secretory organ for inflammation/immune responses and other functions; fourth, LPIs activate transcriptomic remodeling by upregulating 172 transcription factors (TFs), namely, pro-inflammatory factors NR4A3, FOS, KLF3, and HIF1A; fifth, LPIs upregulate 152 nuclear DNA-encoded mitochondrial (mitoCarta) genes, which alter mitochondrial mechanisms and functions, such as mitochondrial organization, respiration, translation, and transport; sixth, LPIs activate reactive oxygen species (ROS) mechanism by upregulating 18 ROS regulators; finally, utilizing the Cytoscape software, we found that three mechanisms, namely, LPI-upregulated TFs, mitoCarta genes, and ROS regulators, are integrated to promote HAEC activation. Our results provide novel insights into aortic EC activation, formulate an EC biology knowledge-based transcriptomic profile strategy, and identify new targets for the development of therapeutics for cardiovascular diseases, inflammatory conditions, immune diseases, organ transplantation, aging, and cancers.
为了确定促炎脂质溶血磷脂酰肌醇（LPI）是否会上调人主动脉内皮细胞（HAEC）激活过程中参与黏附/信号传导的膜蛋白和分泌蛋白的表达，我们开发了一种基于内皮细胞生物学知识的转录组学公式，以全景式分析RNA测序数据。我们有以下主要发现：第一，LPI受体G蛋白偶联受体55（GPR55）在人和小鼠主动脉内皮中均有表达，且在高脂血症中显著上调；第二，LPI上调HAEC中的43种分化簇（CD），促进内皮细胞激活、先天性免疫转分化以及免疫/炎症反应；LPI上调的CD中72.1%在流感病毒、中东呼吸综合征冠状病毒和疱疹病毒感染的人内皮细胞中未被诱导，这提示了LPI在HAEC激活中的特异性；第三，LPI上调640种分泌组基因（SG）的六种类型，即216种经典SG、60种半胱天冬酶-1-gasdermin D（GSDMD）SG、117种半胱天冬酶-4/11-GSDMD SG、40种外泌体SG、179种人类蛋白质图谱（HPA）-细胞因子和28种HPA-趋化因子，这使HAEC成为炎症/免疫反应及其他功能的大型分泌器官；第四，LPI通过上调172种转录因子（TF）激活转录组重塑，这些转录因子包括促炎因子NR4A3、FOS、KLF3和HIF1A；第五，LPI上调152种核DNA编码的线粒体（mitoCarta）基因，这些基因改变线粒体机制和功能，如线粒体组织、呼吸、翻译和运输；第六，LPI通过上调18种ROS调节因子激活活性氧（ROS）机制；最后，利用Cytoscape软件，我们发现LPI上调的TF、mitoCarta基因和ROS调节因子这三种机制相互整合以促进HAEC激活。我们的研究结果为主动脉内皮细胞激活提供了新见解，制定了基于内皮细胞生物学知识的转录组图谱策略，并确定了心血管疾病、炎症性疾病、免疫疾病、器官移植、衰老和癌症治疗药物开发的新靶点。
