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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
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.
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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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