Temporal Transcript Profiling Identifies a Role for Unfolded Protein Stress in Human Gut Ischemia-Reperfusion Injury
| Autor: | 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 |
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| Přispěvatelé: | 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) |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
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 |
| Zdroj: | 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 |
| ISSN: | 2352-345X |
| DOI: | 10.1016/j.jcmgh.2021.11.001 |
| Popis: | 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/gds, accession number GSE37013). Graphical abstract |
| Databáze: | OpenAIRE |
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