title: N-octanoyl dopamine treatment of endothelial cells induces the unfolded protein response and results in hypometabolism and tolerance to hypothermia.
abstract: OBJECTIVE
  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.
authors.affiliation: Vth. Medical Department, Medical Faculty Mannheim, Ruprecht Karls University Heidelberg, Mannheim, Germany.
authors.forename: Eleni
authors.initials: E
authors.lastname: Stamellou
authors.affiliation: Department of Neurosurgery, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Fontana
authors.affiliation: Vth. Medical Department, Medical Faculty Mannheim, Ruprecht Karls University Heidelberg, Mannheim, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Wedel
authors.affiliation: Vth. Medical Department, Medical Faculty Mannheim, Ruprecht Karls University Heidelberg, Mannheim, Germany.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Ntasis
authors.affiliation: Medical Research Centre (ZMF), Medical Faculty Mannheim University of Heidelberg, Mannheim, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Sticht
authors.affiliation: Institute for Molecular and Cellular Biology, Mannheim University of Applied Sciences, Mannheim, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Becker
authors.affiliation: Vth. Medical Department, Medical Faculty Mannheim, Ruprecht Karls University Heidelberg, Mannheim, Germany.
authors.forename: Prama
authors.initials: P
authors.lastname: Pallavi
authors.affiliation: Institute for Molecular and Cellular Biology, Mannheim University of Applied Sciences, Mannheim, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Wolf
authors.affiliation: Vth. Medical Department, Medical Faculty Mannheim, Ruprecht Karls University Heidelberg, Mannheim, Germany.
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Krämer
authors.affiliation: Institute for Molecular and Cellular Biology, Mannheim University of Applied Sciences, Mannheim, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Hafner
authors.affiliation: Department of Nephrology, Academic Medical Centre, Groningen, the Netherlands.
authors.forename: Willem J
authors.initials: WJ
authors.lastname: van Son
authors.affiliation: Vth. Medical Department, Medical Faculty Mannheim, Ruprecht Karls University Heidelberg, Mannheim, Germany.
authors.forename: Benito A
authors.initials: BA
authors.lastname: Yard
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D017209:Apoptosis; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D066298:In Vitro Techniques; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: C554838:N-octanoyldopamine; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; D004298:Dopamine