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N-Octanoyl Dopamine Treatment of Endothelial Cells Induces the Unfolded Protein Response and Results in Hypometabolism and Tolerance to Hypothermia

AIM: N-acyl dopamines (NADD) are gaining attention in the field of inflammatory and neurological disorders. Due to their hydrophobicity, NADD may have access to the endoplasmic reticulum (ER). We therefore investigated if NADD induce the unfolded protein response (UPR) and if this in turn influences...

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Autores principales: Stamellou, Eleni, Fontana, Johann, Wedel, Johannes, Ntasis, Emmanouil, Sticht, Carsten, Becker, Anja, Pallavi, Prama, Wolf, Kerstin, Krämer, Bernhard K., Hafner, Mathias, van Son, Willem J., Yard, Benito A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057113/
https://www.ncbi.nlm.nih.gov/pubmed/24926788
http://dx.doi.org/10.1371/journal.pone.0099298
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author Stamellou, Eleni
Fontana, Johann
Wedel, Johannes
Ntasis, Emmanouil
Sticht, Carsten
Becker, Anja
Pallavi, Prama
Wolf, Kerstin
Krämer, Bernhard K.
Hafner, Mathias
van Son, Willem J.
Yard, Benito A.
author_facet Stamellou, Eleni
Fontana, Johann
Wedel, Johannes
Ntasis, Emmanouil
Sticht, Carsten
Becker, Anja
Pallavi, Prama
Wolf, Kerstin
Krämer, Bernhard K.
Hafner, Mathias
van Son, Willem J.
Yard, Benito A.
author_sort Stamellou, Eleni
collection PubMed
description AIM: N-acyl dopamines (NADD) are gaining attention in the field of inflammatory and neurological disorders. Due to their hydrophobicity, NADD may have access to the endoplasmic reticulum (ER). We therefore investigated if NADD induce the unfolded protein response (UPR) and if this in turn influences cell behaviour. METHODS: Genome wide gene expression profiling, confirmatory qPCR and reporter assays were employed on human umbilical vein endothelial cells (HUVEC) to validate induction of UPR target genes and UPR sensor activation by N-octanoyl dopamine (NOD). Intracellular ATP, apoptosis and induction of thermotolerance were used as functional parameters to assess adaptation of HUVEC. RESULTS: NOD, but not dopamine dose dependently induces the UPR. This was also found for other synthetic NADD. Induction of the UPR was dependent on the redox activity of NADD and was not caused by selective activation of a particular UPR sensor. UPR induction did not result in cell apoptosis, yet NOD strongly impaired cell proliferation by attenuation of cells in the S-G2/M phase. Long-term treatment of HUVEC with low NOD concentration showed decreased intracellular ATP concentration paralleled with activation of AMPK. These cells were significantly more resistant to cold inflicted injury. CONCLUSIONS: We provide for the first time evidence that NADD induce the UPR in vitro. It remains to be assessed if UPR induction is causally associated with hypometabolism and thermotolerance. Further pharmacokinetic studies are warranted to address if the NADD concentrations used in vitro can be obtained in vivo and if this in turn shows therapeutic efficacy.
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spelling pubmed-40571132014-06-18 N-Octanoyl Dopamine Treatment of Endothelial Cells Induces the Unfolded Protein Response and Results in Hypometabolism and Tolerance to Hypothermia Stamellou, Eleni Fontana, Johann Wedel, Johannes Ntasis, Emmanouil Sticht, Carsten Becker, Anja Pallavi, Prama Wolf, Kerstin Krämer, Bernhard K. Hafner, Mathias van Son, Willem J. Yard, Benito A. PLoS One Research Article AIM: N-acyl dopamines (NADD) are gaining attention in the field of inflammatory and neurological disorders. Due to their hydrophobicity, NADD may have access to the endoplasmic reticulum (ER). We therefore investigated if NADD induce the unfolded protein response (UPR) and if this in turn influences cell behaviour. METHODS: Genome wide gene expression profiling, confirmatory qPCR and reporter assays were employed on human umbilical vein endothelial cells (HUVEC) to validate induction of UPR target genes and UPR sensor activation by N-octanoyl dopamine (NOD). Intracellular ATP, apoptosis and induction of thermotolerance were used as functional parameters to assess adaptation of HUVEC. RESULTS: NOD, but not dopamine dose dependently induces the UPR. This was also found for other synthetic NADD. Induction of the UPR was dependent on the redox activity of NADD and was not caused by selective activation of a particular UPR sensor. UPR induction did not result in cell apoptosis, yet NOD strongly impaired cell proliferation by attenuation of cells in the S-G2/M phase. Long-term treatment of HUVEC with low NOD concentration showed decreased intracellular ATP concentration paralleled with activation of AMPK. These cells were significantly more resistant to cold inflicted injury. CONCLUSIONS: We provide for the first time evidence that NADD induce the UPR in vitro. It remains to be assessed if UPR induction is causally associated with hypometabolism and thermotolerance. Further pharmacokinetic studies are warranted to address if the NADD concentrations used in vitro can be obtained in vivo and if this in turn shows therapeutic efficacy. Public Library of Science 2014-06-13 /pmc/articles/PMC4057113/ /pubmed/24926788 http://dx.doi.org/10.1371/journal.pone.0099298 Text en © 2014 Stamellou et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Stamellou, Eleni
Fontana, Johann
Wedel, Johannes
Ntasis, Emmanouil
Sticht, Carsten
Becker, Anja
Pallavi, Prama
Wolf, Kerstin
Krämer, Bernhard K.
Hafner, Mathias
van Son, Willem J.
Yard, Benito A.
N-Octanoyl Dopamine Treatment of Endothelial Cells Induces the Unfolded Protein Response and Results in Hypometabolism and Tolerance to Hypothermia
title N-Octanoyl Dopamine Treatment of Endothelial Cells Induces the Unfolded Protein Response and Results in Hypometabolism and Tolerance to Hypothermia
title_full N-Octanoyl Dopamine Treatment of Endothelial Cells Induces the Unfolded Protein Response and Results in Hypometabolism and Tolerance to Hypothermia
title_fullStr N-Octanoyl Dopamine Treatment of Endothelial Cells Induces the Unfolded Protein Response and Results in Hypometabolism and Tolerance to Hypothermia
title_full_unstemmed N-Octanoyl Dopamine Treatment of Endothelial Cells Induces the Unfolded Protein Response and Results in Hypometabolism and Tolerance to Hypothermia
title_short N-Octanoyl Dopamine Treatment of Endothelial Cells Induces the Unfolded Protein Response and Results in Hypometabolism and Tolerance to Hypothermia
title_sort n-octanoyl dopamine treatment of endothelial cells induces the unfolded protein response and results in hypometabolism and tolerance to hypothermia
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057113/
https://www.ncbi.nlm.nih.gov/pubmed/24926788
http://dx.doi.org/10.1371/journal.pone.0099298
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