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N-octanoyl dopamine treatment of endothelial cells induces the unfolded protein response and results in hypometabolism and tolerance to hypothermia

ABSTRACT: N-octanoyl dopamine (NOD), but not dopamine dose dependently induces the UPR. This was also found for other synthetic N-Acyl dopamine derivates (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. N-octanoyl dopamine (NOD) and other synthetic N-Acyl dopamine derivates (NADD), but not dopamine dose dependently induces the UPR. Long-term treatment of HUVEC with low NOD concentration showed decreased intracellular ATP concentration paralleled with activation of AMPK. 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 NOD

ORGANISM(S): Homo sapiens

SUBMITTER: Benito Yard

PROVIDER: E-GEOD-56285 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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N-octanoyl dopamine treatment of endothelial cells induces the unfolded protein response and results in hypometabolism and tolerance to hypothermia

Project description:N-octanoyl dopamine (NOD), but not dopamine dose dependently induces the UPR. This was also found for other synthetic N-Acyl dopamine derivates (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. N-octanoyl dopamine (NOD) and other synthetic N-Acyl dopamine derivates (NADD), but not dopamine dose dependently induces the UPR. Long-term treatment of HUVEC with low NOD concentration showed decreased intracellular ATP concentration paralleled with activation of AMPK.

2014-03-28 | GSE56285 | GEO

The expression of inflammatory genes in endothelial cells is inhibited by N-octanoyl dopamine via modulation of the NFkB pathway

Project description:Background: Dopamine has intrinsic receptor-independent anti-inflammatory properties when used at high concentrations. Since cellular uptake of N-octanoyl dopamine (NOD) is far better than of dopamine, NOD might display anti-inflammatory effects already at relative low concentrations. The present study was conducted to assess the anti-inflammatory potential of NOD and to elucidate how this was mediated. Methods: Human umbilical vein endothelial cells (HUVECs) were stimulated with TNF-Î± in the presence of various NOD concentrations. Affymetrix gene expression profiling (GEP), Western blotting, adhesion of peripheral blood mononuclear cells (PBMC) to endothelial cells and NFÎºB activation was studied. Compounds that were structurally related to NOD were used to address the molecular entities within NOD that were required for its anti-inflammatory properties. Results: GEP revealed that NOD down-regulates a wide range of pro-inflammatory mediators. Down-regulation of adhesion molecules was confirmed at the protein level and resulted in a decreased adhesion of PBMC to endothelial cells under static and flow conditions. NOD inhibited NFÎºB independently of IÎºBÎ± degradation. Inhibition was associated with an overall decrease in p65 expression and a significant decrease in p65 phosphorylation at Ser276. De novo protein synthesis was not required for inhibition and was not mediated via HO-1. Redox activity and hydrophobicity of NOD seemed to be important entities for its anti-inflammatory properties. Conclusion: Our data demonstrate that NOD has potent anti-inflammatory effects through its action on NFÎºB. Unlike dopamine, NOD has no adverse effects on blood pressure, making it a promising candidate drug to reduce excessive inflammation occurring under various pathological conditions. A total of 6 different HUVEC lines were used, n=3 for each group (TNF or TNF+ NOD).

2012-08-30 | E-GEOD-34059 | biostudies-arrayexpress

The effect of fenofibrate on endothelial cells

Project description:Fenofibrate is a synthetic ligand for the nuclear receptor peroxisome proliferator-activated receptor (PPAR) alpha, but there are reports that fenofibrate affects endothelial cells in PPARa-independent manner. In order to identify PPARa-dependently and PPARa-independently regulated transcripts we generated microarray data from human endothelial cells treated with fenofibrate with and without siRNA-mediated knock-down of PPARa. In this study, we generated microarray data from human umbilical vein endothelial cells (HUVECs) treated with fenofibrate. Time 0 indicates the start point of observation immediately prior to exposure to the 25umol fenofibrate. There are five time points (2, 4, 6, 8, and 18hours) (n=3 at each time point). The control is untreatment HUVEC (n=4).

2010-05-06 | E-GEOD-15483 | biostudies-arrayexpress

Transcription profiling of human HUVEC cell line infected with Neisseria meningitidis wild type and mutants vs uninfected sampled at 3 time points reveals meningococcal adhesion suppresses proapoptotic gene expression and promotes expression of genes supporting early embryonic and cytoprotective signaling of human endothelial cells.

Project description:Time courses of gene expression profiles of primary human umbilical vein endothelial cells (HUVEC) during infection with piliated and adherent wild-type (WT), frpC/frpA-deficient mutant, or the non-adherent (?pilD) Neisseria meningitidis MC58 bacteria defective in production of the type IV pilus, were analyzed respectively. Total RNA isolated from uninfected HUVEC (reference) and HUVEC after 1, 4 or 6 hours of infection with N. meningitidis mutants was labeled according to standard Affymetrix protocol and hybridized to HG-U133A GeneChips. Data were analyzed by Robust Multi-array Analysis algorithm. For every condition at least two biological replicates were analyzed, totally representing 23 Affymetrix GeneChips.

2007-10-26 | E-GEOD-4646 | biostudies-arrayexpress

HUVECs with endogenous or overexpressed GPR4 treated with pH 8.4 (control) or pH 6.4 for 5 h

Project description:Acidic tissue microenvironment is commonly found in a variety of pathophysiological conditions. GPR4 is a proton-sensing G protein-coupled receptor that is fully activated by acidic extracellular pH but has lesser activity at the physiological pH 7.4 and minimal activity at more alkaline pH. To determine the effects of GPR4 activation by acidosis on vascular endothelial cells, we examined the global gene expression of the acidosis response in primary human umbilical vein endothelial cells (HUVEC) with varying level of GPR4. HUVEC with endogenous or overexpressed GPR4 level (designated as HUVEC/Vector & HUVEC/GPR4 cells). Two treatment conditions: pH 6.4 vs. pH 8.4 for 5 h. Biological replicates: 4 HUVEC/Vector replicates (pH6.4 vs pH 8.4), and 4 HUVEC/GPR4 replicates (pH6.4 vs pH 8.4).

2013-04-25 | E-GEOD-40060 | biostudies-arrayexpress

Gene array analysis of Human Umbilical Vein Endothelial Cells (HUVEC) transduced with lentivirus containing cDNA of NKX2,5 or GATA4 or GFP.

Project description:The aim of this study was to induce cardiomyogenic conversion of Human Umbilical Vein Endothelial Cells (HUVEC ) by triggering ectopic expression of the cardiac transcription factors Nkx2.5 and GATA4. Cells were cultured without cell myocardial co-culture system and transduced with lentivirus containing coding sequence of Nkx2.5, GATA4 or GFP as control. Cells were cultured in the EBM-2/ EGM-2 medium, 12 days before microarray analysis. We report in this study that over-expression of NKX2.5 and GATA4 in HUVECs stimulates the expression of some specific genes important in the cardiomyogenic differentiation process, leading to partial switch of these cells from the endothelial to the myocardial course. 12 arrays were analysed. Three competitive hybridizations to the arrays were performed in duplicate using each time, two dye-swap following this experimental design: AWA065 : CY5 (HUVEC+NKX2,5) / CY3 (HUVEC) AWA067 : CY5 (HUVEC) / CY3 (HUVEC+NKX2,5) AWA075 : CY5 (HUVEC+NKX2,5) / CY3 (HUVEC) AWA076 : CY5 (HUVEC) / CY3 (HUVEC+NKX2,5) AWA068 : CY5 ((HUVEC) / CY3 (HUVEC+GATA4) AWA070 : CY5 (HUVEC+GATA4) / CY3 ((HUVEC) AWA073 : CY5 (HUVEC+GATA4) / CY3 ((HUVEC) AWA002 : CY5 ((HUVEC) / CY3 (HUVEC+GATA4) AWA066 : CY5 (HUVEC) / CY3 (HUVEC+NKX2.5+GATA4) AWA069 : CY5 (HUVEC+NKX2.5+GATA4) / CY3 (HUVEC) AWA071 : CY5 (HUVEC+NKX2.5+GATA4) / CY3 (HUVEC) AWA074 ; CY5 (HUVEC) / CY3 (HUVEC+NKX2.5+GATA4)

2012-04-20 | E-GEOD-37459 | biostudies-arrayexpress

Compound C prevents the unfolded protein response during glucose deprivation through a mechanism independent of AMPK and BMP signaling.

Project description:Inhibiting the unfolded protein response (UPR) can be a therapeutic approach, especially for targeting the tumor microenvironment. We found that compound C (also known as dorsomorphin) prevented the UPR and exerted enhanced cytotoxicity during glucose deprivation. The UPR-inhibiting activity of compound C was not associated with either AMPK or BMP signaling inhibition. To induce the UPR, we treated HT1080 cells for 18 hours under ER stress conditions by adding 10 mM 2-Deoxy-D-glucose (2DG) to culture medium. UPR inhibitors (compound C, versipelostatin and phenformin) were added just before 2DG was added in medium. Total 8 samples were prepared for RNA extraction and hybridization on Affymetrix microarrays.

2012-10-11 | E-GEOD-32911 | biostudies-arrayexpress

The expression of inflammatory genes in endothelial cells is inhibited by N-octanoyl dopamine via modulation of the NFkB pathway

Project description:Background: Dopamine has intrinsic receptor-independent anti-inflammatory properties when used at high concentrations. Since cellular uptake of N-octanoyl dopamine (NOD) is far better than of dopamine, NOD might display anti-inflammatory effects already at relative low concentrations. The present study was conducted to assess the anti-inflammatory potential of NOD and to elucidate how this was mediated. Methods: Human umbilical vein endothelial cells (HUVECs) were stimulated with TNF-α in the presence of various NOD concentrations. Affymetrix gene expression profiling (GEP), Western blotting, adhesion of peripheral blood mononuclear cells (PBMC) to endothelial cells and NFκB activation was studied. Compounds that were structurally related to NOD were used to address the molecular entities within NOD that were required for its anti-inflammatory properties. Results: GEP revealed that NOD down-regulates a wide range of pro-inflammatory mediators. Down-regulation of adhesion molecules was confirmed at the protein level and resulted in a decreased adhesion of PBMC to endothelial cells under static and flow conditions. NOD inhibited NFκB independently of IκBα degradation. Inhibition was associated with an overall decrease in p65 expression and a significant decrease in p65 phosphorylation at Ser276. De novo protein synthesis was not required for inhibition and was not mediated via HO-1. Redox activity and hydrophobicity of NOD seemed to be important entities for its anti-inflammatory properties. Conclusion: Our data demonstrate that NOD has potent anti-inflammatory effects through its action on NFκB. Unlike dopamine, NOD has no adverse effects on blood pressure, making it a promising candidate drug to reduce excessive inflammation occurring under various pathological conditions.

2012-08-30 | GSE34059 | GEO

Compound C prevents the unfolded protein response during glucose deprivation through a mechanism independent of AMPK and BMP signaling.

2012-10-11 | GSE32911 | GEO

c-MYC target genes in HUVEC

Project description:siRNA mediated knock-down of c-MYC vs. scrambled control in human umbilical vein endothelial cells (HUVEC).

2016-01-11 | E-MTAB-4025 | biostudies-arrayexpress