Temporal Transcript Profiling Identifies a Role for Unfolded Protein Stress in Human Gut Ischemia-Reperfusion Injury
| العنوان: | Temporal Transcript Profiling Identifies a Role for Unfolded Protein Stress in Human Gut Ischemia-Reperfusion Injury |
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| المؤلفون: | Kaatje Lenaerts, Joep Grootjans, Anna M. Kip, Marco Manca, Steven W.M. Olde Damink, Bas Boonen, Cornelis H. C. Dejong, Wim A. Buurman, M'hamed Hadfoune, Joep P. M. Derikx, Erik A.L. Biessen |
| المساهمون: | Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Paediatric Surgery, ARD - Amsterdam Reproduction and Development, RS: NUTRIM - R2 - Liver and digestive health, Surgery, Pathologie, RS: Carim - B07 The vulnerable plaque: makers and markers, MUMC+: MA Heelkunde (9) |
| المصدر: | CMGH, 13(3), 681-694. Elsevier Inc. Cellular and Molecular Gastroenterology and Hepatology : CMGH 13(3), 681-694 (2022). doi:10.1016/j.jcmgh.2021.11.001 Cellular and molecular gastroenterology and hepatology, 13(3), 681-694. Elsevier Inc. Cellular and Molecular Gastroenterology and Hepatology |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | ATF4, activating transcription factor 4, CELL-SURVIVAL, eIF2α, eukaryotic translation initiation factor 2A, INDUCED INFLAMMATION, mEGF, mouse epidermal growth factor, EM, Electron microscopy, ROCK, Rho kinase, Intestinal Ischemia-Reperfusion, GADD34, growth arrest and DNA-damage-inducible protein, Transcriptome, ACTIVATION, UPR, unfolded protein response, ENDOPLASMIC-RETICULUM STRESS, Gene expression, I, ischemia, Original Research, Human Intestinal Organoids, Gastroenterology, DEATH, CHOP, CCAAT/enhancer-binding protein homologous protein, BiP, binding immunoglobulin protein, Endoplasmic Reticulum Stress, Cell biology, medicine.anatomical_structure, XBP1, X-box binding protein 1, Reperfusion Injury, JNK, c-Jun N-terminal kinase, qPCR, quantitative polymerase chain reaction, R, reperfusion, HYPOXIA-INDUCIBLE FACTOR, FACTOR-I, NF-κB, nuclear factor-κB, IRE1, inositol-requiring enzyme 1, KAPPA-B, Biology, KEGG, Kyoto Encyclopedia of Genes and Genomes, ER, endoplasmic reticulum, Organoid, medicine, KINASE, Integrated stress response, Humans, C, control, Transcriptomics, GO, gene ontology, Hepatology, Microarray analysis techniques, XBP1s, spliced X-box binding protein 1, Endoplasmic reticulum, PERK, protein kinase R-like ER kinase, Activating Transcription Factor 4, Small intestine, ISRIB, integrated stress response inhibitor, ER, Unfolded protein response, Unfolded Protein Response, HIF1A, hypoxia-inducible factor 1-α, Transcription Factor CHOP, MAPK, mitogen-activated protein kinase |
| الوصف: | Background & Aims Intestinal ischemia-reperfusion injury is a serious and life-threatening condition. A better understanding of molecular mechanisms related to intestinal ischemia-reperfusion injury in human beings is imperative to find therapeutic targets and improve patient outcome. Methods First, the in vivo dynamic modulation of mucosal gene expression of the ischemia-reperfusion–injured human small intestine was studied. Based on functional enrichment analysis of the changing transcriptome, one of the predominantly regulated pathways was selected for further investigation in an in vitro human intestinal organoid model. Results Ischemia-reperfusion massively changed the transcriptional landscape of the human small intestine. Functional enrichment analysis based on gene ontology and pathways pointed to the response to unfolded protein as a predominantly regulated process. In addition, regulatory network analysis identified hypoxia-inducing factor 1A as one of the key mediators of ischemia-reperfusion–induced changes, including the unfolded protein response (UPR). Differential expression of genes involved in the UPR was confirmed using quantitative polymerase chain reaction analysis. Electron microscopy showed signs of endoplasmic reticulum stress. Collectively, these findings point to a critical role for unfolded protein stress in intestinal ischemia-reperfusion injury in human beings. In a human intestinal organoid model exposed to hypoxia-reoxygenation, attenuation of UPR activation with integrated stress response inhibitor strongly reduced pro-apoptotic activating transcription factor 4 (ATF4)-CCAAT/enhancer-binding protein homologous protein (CHOP) signaling. Conclusions Transcriptome analysis showed a crucial role for unfolded protein stress in the response to ischemia-reperfusion in human small intestine. UPR inhibition during hypoxia-reoxygenation in an intestinal organoid model suggests that downstream protein kinase R-like ER kinase (PERK) signaling may be a promising target to reduce intestinal ischemia-reperfusion injury. Microarray data are available in GEO (https://www.ncbi.nlm.nih.gov/gdsTest, accession number GSE37013). Graphical abstract |
| اللغة: | English |
| تدمد: | 2352-345X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::76ba4ffc78867321b72f85db21a76d04Test http://www.scopus.com/inward/record.url?scp=85121206348&partnerID=8YFLogxKTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....76ba4ffc78867321b72f85db21a76d04 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 2352345X |
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