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dc.creatorLu, Yifan
dc.creatorNanayakkara, Gayani
dc.creatorSun, Yu
dc.creatorLiu, Lu
dc.creatorXU, KEMAN
dc.creatorDrummer, Charles, IV
dc.creatorShao, Ying
dc.creatorSaaoud, Fatma
dc.creatorChoi, Eric T.
dc.creatorJiang, Xiahua
dc.creatorWang, Hong
dc.creatorYang, Xiaofeng
dc.date.accessioned2022-04-29T19:21:46Z
dc.date.available2022-04-29T19:21:46Z
dc.date.issued2021-09-28
dc.identifier.issn2213-2317
dc.identifier.doihttp://dx.doi.org/10.34944/dspace/7611
dc.identifier.urihttp://hdl.handle.net/20.500.12613/7633
dc.description.abstractTo determine the roles of nuclear localization of pro-caspase-1 in human aortic endothelial cells (HAECs) activated by proatherogenic lipid lysophosphatidylcholine (LPC), we examined cytosolic and nuclear localization of pro-caspase-1, identified nuclear export signal (NES) in pro-caspase-1 and sequenced RNAs. We made the following findings: 1) LPC increases nuclear localization of procaspase-1 in HAECs. 2) Nuclear pro-caspase-1 exports back to the cytosol, which is facilitated by a leptomycin B-inhibited mechanism. 3) Increased nuclear localization of pro-caspase-1 by a new NES peptide inhibitor upregulates inflammatory genes in oxidative stress and Th17 pathways; and SUMO activator N106 enhances nuclear localization of pro-caspase-1 and caspase-1 activation (p20) in the nucleus. 4) LPC plus caspase-1 enzymatic inhibitor upregulates inflammatory genes with hypercytokinemia/hyperchemokinemia and interferon pathways, suggesting a novel capsase-1 enzyme-independent inflammatory mechanism. 5) LPC in combination with NES inhibitor and caspase-1 inhibitor upregulate inflammatory gene expression that regulate Th17 activation, endotheli-1 signaling, p38-, and ERK- MAPK pathways. To examine two hallmarks of endothelial activation such as secretomes and membrane protein signaling, LPC plus NES inhibitor upregulate 57 canonical secretomic genes and 76 exosome secretomic genes, respectively, promoting four pathways including Th17, IL-17 promoted cytokines, interferon signaling and cholesterol biosynthesis. LPC with NES inhibitor also promote inflammation via upregulating ROS promoter CYP1B1 and 11 clusters of differentiation (CD) membrane protein pathways. Mechanistically, all the LPC plus NES inhibitor-induced genes are significantly downregulated in CYP1B1-deficient microarray, suggesting that nuclear caspase-1-induced CYP1B1 promotes strong inflammation. These transcriptomic results provide novel insights on the roles of nuclear caspase-1 in sensing DAMPs, inducing ROS promoter CYP1B1 and in regulating a large number of genes that mediate HAEC activation and inflammation. These findings will lead to future development of novel therapeutics for cardiovascular diseases (CVD), inflammations, infections, transplantation, autoimmune disease and cancers. (total words: 284).
dc.format.extent18 pages
dc.languageEnglish
dc.language.isoeng
dc.relation.ispartofFaculty/ Researcher Works
dc.relation.haspartRedox Biology, Vol. 47
dc.relation.isreferencedbyElsevier
dc.rightsAttribution-NonCommercial-NoDerivs CC BY-NC-ND
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectNuclear localization
dc.subjectCaspase-1
dc.subjectAortic endothelial cell
dc.subjectInflammation
dc.subjectSecretomes
dc.titleProcaspase-1 patrolled to the nucleus of proatherogenic lipid LPC-activated human aortic endothelial cells induces ROS promoter CYP1B1 and strong inflammation
dc.typeText
dc.type.genreJournal article
dc.contributor.groupCenter of Cardiovascular Research (Temple University)
dc.contributor.groupCenter of Inflammation and Lung Research (Temple University)
dc.description.departmentSurgery
dc.description.departmentCardiovascular Sciences
dc.relation.doihttps://doi.org/10.1016/j.redox.2021.102142
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.description.schoolcollegeLewis Katz School of Medicine
dc.creator.orcidXu|0000-0002-0816-1760
dc.creator.orcidShao|0000-0001-5879-0154
dc.creator.orcidWang|0000-0001-6258-4070
dc.creator.orcidYang|0000-0002-6854-6195
dc.temple.creatorLu, Yifan
dc.temple.creatorNanayakkara, Gayani
dc.temple.creatorSun, Yu
dc.temple.creatorLiu, Lu
dc.temple.creatorXu, Keman
dc.temple.creatorDrummer IV, Charles
dc.temple.creatorShao, Ying
dc.temple.creatorSaaoud, Fatma
dc.temple.creatorChoi, Eric T.
dc.temple.creatorJiang, Xiahua
dc.temple.creatorWang, Hong
dc.temple.creatorYang, Xiaofeng
refterms.dateFOA2022-04-29T19:21:46Z


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