{"doi":"10.3389/fcvm.2021.773473","title":"Novel Knowledge-Based Transcriptomic Profiling of Lipid Lysophosphatidylinositol-Induced Endothelial Cell Activation","abstract":"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.","journal":"Frontiers in Cardiovascular Medicine","year":2021,"id":173949,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9448,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":237315,"name":"Ying Shao","orcid":"0000-0001-5879-0154","position":1,"is_corresponding":false},{"id":239127,"name":"Fatma Saaoud","orcid":null,"position":2,"is_corresponding":false},{"id":713525,"name":"Aria Gillespie","orcid":null,"position":3,"is_corresponding":false},{"id":237314,"name":"Charles Drummer","orcid":"0000-0001-9059-1454","position":4,"is_corresponding":false},{"id":712772,"name":"Lu Liu","orcid":"0000-0002-6233-0705","position":5,"is_corresponding":false},{"id":237313,"name":"Yifan Lu","orcid":"0000-0003-4461-0698","position":6,"is_corresponding":false},{"id":237312,"name":"Yu Sun","orcid":"0000-0002-0877-7186","position":7,"is_corresponding":false},{"id":713526,"name":"Hang Xi","orcid":null,"position":8,"is_corresponding":false},{"id":291657,"name":"Çağla Tükel","orcid":"0000-0001-7073-0226","position":9,"is_corresponding":false},{"id":588313,"name":"Domenico Praticò","orcid":"0000-0002-8347-613X","position":10,"is_corresponding":false},{"id":237300,"name":"Xuebin Qin","orcid":"0000-0001-9875-983X","position":11,"is_corresponding":false},{"id":376537,"name":"Jianxin Sun","orcid":"0000-0001-5319-912X","position":12,"is_corresponding":false},{"id":286976,"name":"Eric T. 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