Temporal Transcript Profiling Identifies a Role for Unfolded Protein Stress in Human Gut Ischemia-Reperfusion Injury
Cellular and Molecular Gastroenterology and Hepatology, vol. 13, pp. 681–694
Abstract
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).
Authors 11
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Affiliation as printed
Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
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Affiliation as printed
Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
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Maastricht University Medical Centre · Maastricht University
Affiliation as printed
Department of Pathology, CARIM School for Cardiovascular Diseases, Maastricht University Medical Center+, Maastricht, the Netherlands
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Affiliation as printed
Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
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Affiliation as printed
Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
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Maastricht University · Emma Kinderziekenhuis · Amsterdam University Medical Centers · Vrije Universiteit Amsterdam · University of Amsterdam
Affiliation as printed
Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands; Department of Pediatric Surgery, Emma Children's Hospital, Amsterdam University Medical Center, University of Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
Department of Pediatric Surgery, Emma Children's Hospital, Amsterdam University Medical Center, University of Amsterdam, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
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Maastricht University Medical Centre · Maastricht University · Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Department of Pathology, CARIM School for Cardiovascular Diseases, Maastricht University Medical Center+, Maastricht, the Netherlands; Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University Hospital, Aachen, Germany
Department of Pathology, CARIM School for Cardiovascular Diseases, Maastricht University Medical Center+, Maastricht, the Netherlands
Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University Hospital, Aachen, Germany
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Maastricht University · Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands; Department of General, Visceral, and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
Department of General, Visceral, and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
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Maastricht University · Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands; Department of General, Visceral, and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
Department of General, Visceral, and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
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Affiliation as printed
Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
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Kaatje Lenaerts corresponding
Affiliation as printed
Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands. Electronic address: kaatje.lenaerts@maastrichtuniversity.nl
Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
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