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.

Aorta- and liver-generated TMAO enhances trained immunity for increased inflammation via ER stress/mitochondrial ROS/glycolysis pathways

“…We hypothesized that TMAO promotes innate immune trans-differentiation of HAECs. We used a novel knowledge-based transcriptomic profiling approach and Venn diagram analysis of TMAO-upregulated genes with 1249 Ingenuity Pathway Analysis (IPA) designed cytokine/chemokine genes, 4340 canonical secretomic genes, and noncanonical secretomic genes including 964 caspase-1-gasdermin D secretomes and 1223 caspase-4 (humans)/11 (mice) secretomes, and 6560 exosome secretomic genes (71)(72)(73)(74). We found that 11 cytokines/chemokines (Figures 5A), 19 canonical/noncanonical secretomic genes (Figures 5B), and 22 exosome secretomic genes (Figures 5C) were overlapped with the TMAO-upregulated genes (RNA-seq).…”

Membrane-bound O-acyltransferase 7 (MBOAT7)-driven phosphatidylinositol remodeling in advanced liver disease

“…These bioactive lysophospholipids act primarily by binding to dedicated cell surface receptors in the G protein-coupled receptor family to elicit cellular signaling responses (80,87,88). Although a plethora of research has been conducted with lysophosphatidic acid and sphingosine-1-phosphate, there is emerging evidence that LPI lipids can also serve as relevant lipid signals promoting proinflammatory, profibrotic, and endothelial-activating effects (37,(89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99)(100)(101)(102). Several recent articles have shown that the MBOAT7 substrate LPIs (16:0, 18:0 LPI, and 18:1 LPI) can initiate rapid signaling processes in macrophages and endothelial cells to promote inflammatory cytokine production as well as endothelial cell activation (89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99)(100)(101)(102).…”

“…Although a plethora of research has been conducted with lysophosphatidic acid and sphingosine-1-phosphate, there is emerging evidence that LPI lipids can also serve as relevant lipid signals promoting proinflammatory, profibrotic, and endothelial-activating effects (37,(89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99)(100)(101)(102). Several recent articles have shown that the MBOAT7 substrate LPIs (16:0, 18:0 LPI, and 18:1 LPI) can initiate rapid signaling processes in macrophages and endothelial cells to promote inflammatory cytokine production as well as endothelial cell activation (89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99)(100)(101)(102). Given that ASO-mediated knockdown of Mboat7 resulted in the accumulation of LPI lipids in the liver (37,38,40), Helsley et al followed up on this observation to demonstrate that only two intraperitoneal doses of exogenous 18:0 LPI or 18:1 LPI were able to stimulate proinflammatory and profibrotic gene expression in the liver in Mboat7 knockdown mice but not in control mice where MBOAT7 activity is sufficient to esterify the exogenous LPI (37).…”

Editorial: Insights in cardiovascular therapeutics: 2021 – cell death, cardiovascular injuries, and novel targets of cardiovascular therapeutics

“…Previous studies reported that lysophosphatidylcholine (LPC) and oxidized low-density lipoprotein (oxLDL) induce Nod-like receptor family 3 (NLRP3) and promote endothelial cell activation ( 26 – 28 ) in cardiac diseases ( 29 ). Further, the activation of caspase-1 canonical inflammasome pathway and caspase-4 (human)/ caspase-11 (mice) noncanonical inflammasome pathway will lead to gasdermin D cleavage and N-terminal gasdermin D protein pore formation on the plasma membrane, which could mediate endothelial pyroptosis during atherosclerosis development ( 30 – 32 ). In addition to pyroptosis, necroptosis, and mitochondrially mediated necrosis are the other common cell death pathways observed in heart diseases.…”