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Modeling the Effects of Severe Metabolic Disease by Genome Editing of hPSC-Derived Endothelial Cells Reveals an Inflammatory Phenotype
The kinase AKT2 (PKB) is an important mediator of insulin signaling, for which loss-of-function knockout (KO) mutants lead to early onset diabetes mellitus, and dominant active mutations lead to early development of obesity and endothelial cell (EC) dysfunction. To model EC dysfunction, we used edit...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940871/ https://www.ncbi.nlm.nih.gov/pubmed/31835296 http://dx.doi.org/10.3390/ijms20246201 |
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author | Roudnicky, Filip Lan, Yanjun Friesen, Max Dernick, Gregor Zhang, Jitao David Staempfli, Andreas Bordag, Natalie Wagner-Golbs, Antje Christensen, Klaus Ebeling, Martin Graf, Martin Burcin, Mark Meyer, Claas Aiko Cowan, Chad A Patsch, Christoph |
author_facet | Roudnicky, Filip Lan, Yanjun Friesen, Max Dernick, Gregor Zhang, Jitao David Staempfli, Andreas Bordag, Natalie Wagner-Golbs, Antje Christensen, Klaus Ebeling, Martin Graf, Martin Burcin, Mark Meyer, Claas Aiko Cowan, Chad A Patsch, Christoph |
author_sort | Roudnicky, Filip |
collection | PubMed |
description | The kinase AKT2 (PKB) is an important mediator of insulin signaling, for which loss-of-function knockout (KO) mutants lead to early onset diabetes mellitus, and dominant active mutations lead to early development of obesity and endothelial cell (EC) dysfunction. To model EC dysfunction, we used edited human pluripotent stem cells (hPSCs) that carried either a homozygous deletion of AKT2 (AKT2 KO) or a dominant active mutation (AKT2 E17K), which, along with the parental wild type (WT), were differentiated into ECs. Profiling of EC lines indicated an increase in proinflammatory and a reduction in anti-inflammatory fatty acids, an increase in inflammatory chemokines in cell supernatants, increased expression of proinflammatory genes, and increased binding to the EC monolayer in a functional leukocyte adhesion assay for both AKT2 KO and AKT2 E17K. Collectively, these findings suggest that vascular endothelial inflammation that results from dysregulated insulin signaling (homeostasis) may contribute to coronary artery disease, and that either downregulation or upregulation of the insulin pathway may lead to inflammation of endothelial cells. This suggests that the standard of care for patients must be expanded from control of metabolic parameters to include control of inflammation, such that endothelial dysfunction and cardiovascular disorders can ultimately be prevented. |
format | Online Article Text |
id | pubmed-6940871 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-69408712020-01-09 Modeling the Effects of Severe Metabolic Disease by Genome Editing of hPSC-Derived Endothelial Cells Reveals an Inflammatory Phenotype Roudnicky, Filip Lan, Yanjun Friesen, Max Dernick, Gregor Zhang, Jitao David Staempfli, Andreas Bordag, Natalie Wagner-Golbs, Antje Christensen, Klaus Ebeling, Martin Graf, Martin Burcin, Mark Meyer, Claas Aiko Cowan, Chad A Patsch, Christoph Int J Mol Sci Article The kinase AKT2 (PKB) is an important mediator of insulin signaling, for which loss-of-function knockout (KO) mutants lead to early onset diabetes mellitus, and dominant active mutations lead to early development of obesity and endothelial cell (EC) dysfunction. To model EC dysfunction, we used edited human pluripotent stem cells (hPSCs) that carried either a homozygous deletion of AKT2 (AKT2 KO) or a dominant active mutation (AKT2 E17K), which, along with the parental wild type (WT), were differentiated into ECs. Profiling of EC lines indicated an increase in proinflammatory and a reduction in anti-inflammatory fatty acids, an increase in inflammatory chemokines in cell supernatants, increased expression of proinflammatory genes, and increased binding to the EC monolayer in a functional leukocyte adhesion assay for both AKT2 KO and AKT2 E17K. Collectively, these findings suggest that vascular endothelial inflammation that results from dysregulated insulin signaling (homeostasis) may contribute to coronary artery disease, and that either downregulation or upregulation of the insulin pathway may lead to inflammation of endothelial cells. This suggests that the standard of care for patients must be expanded from control of metabolic parameters to include control of inflammation, such that endothelial dysfunction and cardiovascular disorders can ultimately be prevented. MDPI 2019-12-09 /pmc/articles/PMC6940871/ /pubmed/31835296 http://dx.doi.org/10.3390/ijms20246201 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Roudnicky, Filip Lan, Yanjun Friesen, Max Dernick, Gregor Zhang, Jitao David Staempfli, Andreas Bordag, Natalie Wagner-Golbs, Antje Christensen, Klaus Ebeling, Martin Graf, Martin Burcin, Mark Meyer, Claas Aiko Cowan, Chad A Patsch, Christoph Modeling the Effects of Severe Metabolic Disease by Genome Editing of hPSC-Derived Endothelial Cells Reveals an Inflammatory Phenotype |
title | Modeling the Effects of Severe Metabolic Disease by Genome Editing of hPSC-Derived Endothelial Cells Reveals an Inflammatory Phenotype |
title_full | Modeling the Effects of Severe Metabolic Disease by Genome Editing of hPSC-Derived Endothelial Cells Reveals an Inflammatory Phenotype |
title_fullStr | Modeling the Effects of Severe Metabolic Disease by Genome Editing of hPSC-Derived Endothelial Cells Reveals an Inflammatory Phenotype |
title_full_unstemmed | Modeling the Effects of Severe Metabolic Disease by Genome Editing of hPSC-Derived Endothelial Cells Reveals an Inflammatory Phenotype |
title_short | Modeling the Effects of Severe Metabolic Disease by Genome Editing of hPSC-Derived Endothelial Cells Reveals an Inflammatory Phenotype |
title_sort | modeling the effects of severe metabolic disease by genome editing of hpsc-derived endothelial cells reveals an inflammatory phenotype |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940871/ https://www.ncbi.nlm.nih.gov/pubmed/31835296 http://dx.doi.org/10.3390/ijms20246201 |
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