PMID- 27179975
OWN - NLM
STAT- MEDLINE
DCOM- 20170502
LR  - 20220722
IS  - 1873-2968 (Electronic)
IS  - 0006-2952 (Linking)
VI  - 110-111
DP  - 2016 Jun 15
TI  - Role of UCP2 in the protective effects of PPARbeta/delta activation on 
      lipopolysaccharide-induced endothelial dysfunction.
PG  - 25-36
LID - S0006-2952(16)30077-6 [pii]
LID - 10.1016/j.bcp.2016.05.004 [doi]
AB  - Bacterial endotoxin lipopolysaccharide (LPS) activates inflammatory pathways, 
      induces cytokine expression in the endothelium, augments reactive oxygen species 
      (ROS) production in the vascular wall, and induces endothelial dysfunction. The 
      aim of the present study was to analyze the effects of peroxisome 
      proliferator-activated receptor (PPAR)beta/delta activation on LPS-induced inflammation, 
      oxidative stress and endothelial dysfunction and to determine whether uncoupling 
      protein-2 (UCP2) plays a role in these effects. In vivo, the PPARbeta/delta agonist 
      GW0742 treatment prevented the LPS-induced reduction in aortic relaxation, the 
      increase in vascular ROS production, the upregulation of NOX1, NOX2, p47(phox), 
      and p22(phox) mRNA levels, and the endoplasmic reticulum (ER) stress markers in 
      mice. We show that in mouse aortic endothelial cells (MAECs), GW0742 prevented 
      the decreased A23187-stimulated nitric oxide (NO) production, and the increased 
      intracellular ROS levels caused by exposure to LPS in vitro. The PPARbeta/delta 
      antagonist GSK0660 abolished all these in vivo and in vitro protective effects 
      induced by GW0742. This agonist also restored the reduced expression of UCP2 and 
      mitofusin-2 induced by LPS. The effects of GW0742 on NO and ROS production in 
      MAEC exposed to LPS were abolished by the UCP2 inhibitor genipin or by siRNA 
      targeting UCP-2. Genipin also suppressed the expressional changes on NADPH 
      oxidase and ER stress markers induced by GW0742. In conclusion, PPARbeta/delta 
      activation restored the LPS-induced endothelial dysfunction by upregulation of 
      UCP2, with the subsequent alleviation of ER stress and NADPH oxidase activity, 
      thus reducing intracellular ROS production and increasing NO bioavailability.
CI  - Copyright (c) 2016 Elsevier Inc. All rights reserved.
FAU - Toral, Marta
AU  - Toral M
AD  - Department of Pharmacology, School of Pharmacy, University of Granada, 18071 
      Granada, Spain.
FAU - Romero, Miguel
AU  - Romero M
AD  - Department of Pharmacology, School of Pharmacy, University of Granada, 18071 
      Granada, Spain; Instituto de Investigacion Biosanitaria de Granada, ibs.GRANADA, 
      Granada, Spain.
FAU - Jimenez, Rosario
AU  - Jimenez R
AD  - Department of Pharmacology, School of Pharmacy, University of Granada, 18071 
      Granada, Spain; Instituto de Investigacion Biosanitaria de Granada, ibs.GRANADA, 
      Granada, Spain.
FAU - Robles-Vera, Inaki
AU  - Robles-Vera I
AD  - Department of Pharmacology, School of Pharmacy, University of Granada, 18071 
      Granada, Spain.
FAU - Tamargo, Juan
AU  - Tamargo J
AD  - Department of Pharmacology, School of Medicine, University Complutense of Madrid, 
      Madrid, Spain.
FAU - Martinez, Maria Carmen
AU  - Martinez MC
AD  - INSERM U1063, Sopam, Angers University, F-49045 Angers, France.
FAU - Perez-Vizcaino, Francisco
AU  - Perez-Vizcaino F
AD  - Department of Pharmacology, School of Medicine, University Complutense of Madrid, 
      Madrid, Spain; CIBER de Enfermedades Respiratorias, CIBERES, Madrid, Spain.
FAU - Duarte, Juan
AU  - Duarte J
AD  - Department of Pharmacology, School of Pharmacy, University of Granada, 18071 
      Granada, Spain; Instituto de Investigacion Biosanitaria de Granada, ibs.GRANADA, 
      Granada, Spain. Electronic address: jmduarte@ugr.es.
LA  - eng
PT  - Journal Article
DEP - 20160512
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Cytochrome b Group)
RN  - 0 (GSK0660)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (PPAR gamma)
RN  - 0 (PPAR-beta)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Sulfones)
RN  - 0 (Thiazoles)
RN  - 0 (Thiophenes)
RN  - 0 (Ucp2 protein, mouse)
RN  - 0 (Uncoupling Protein 2)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 37H9VM9WZL (Calcimycin)
RN  - 4PZK9FJC4Z 
      ((4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic 
      acid)
RN  - EC 1.6.- (NADH, NADPH Oxidoreductases)
RN  - EC 1.6.3.- (Cybb protein, mouse)
RN  - EC 1.6.3.- (NADPH Oxidase 1)
RN  - EC 1.6.3.- (NADPH Oxidase 2)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 1.6.3.- (NOX1 protein, mouse)
RN  - EC 1.6.3.1 (Cyba protein, mouse)
RN  - EC 1.6.3.1 (neutrophil cytosolic factor 1)
SB  - IM
MH  - Animals
MH  - Aorta/cytology/drug effects/metabolism
MH  - Calcimycin/pharmacology
MH  - Cytochrome b Group/genetics/metabolism
MH  - Endoplasmic Reticulum Stress/drug effects/genetics
MH  - Endothelial Cells/cytology/drug effects/*metabolism
MH  - Endothelium, Vascular/cytology/drug effects/*metabolism
MH  - Gene Expression Regulation
MH  - Inflammation/chemically induced/genetics/pathology/prevention & control
MH  - Lipopolysaccharides/pharmacology
MH  - Male
MH  - Membrane Glycoproteins/genetics/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - NADH, NADPH Oxidoreductases/genetics/metabolism
MH  - NADPH Oxidase 1
MH  - NADPH Oxidase 2
MH  - NADPH Oxidases/genetics/metabolism
MH  - Nitric Oxide/metabolism
MH  - PPAR gamma/agonists/antagonists & inhibitors/genetics/*metabolism
MH  - PPAR-beta/agonists/antagonists & inhibitors/genetics/*metabolism
MH  - Primary Cell Culture
MH  - RNA, Small Interfering/genetics/metabolism
MH  - Reactive Oxygen Species/agonists/antagonists & inhibitors/metabolism
MH  - Signal Transduction
MH  - Sulfones/pharmacology
MH  - Thiazoles/pharmacology
MH  - Thiophenes/pharmacology
MH  - Tissue Culture Techniques
MH  - Uncoupling Protein 2/antagonists & inhibitors/genetics/*metabolism
OTO - NOTNLM
OT  - ER stress
OT  - Endothelial dysfunction
OT  - NADPH oxidase
OT  - Oxidative stress
OT  - PPARbeta/delta
OT  - UCP2
EDAT- 2016/05/18 06:00
MHDA- 2017/05/04 06:00
CRDT- 2016/05/16 06:00
PHST- 2016/03/17 00:00 [received]
PHST- 2016/05/10 00:00 [accepted]
PHST- 2016/05/16 06:00 [entrez]
PHST- 2016/05/18 06:00 [pubmed]
PHST- 2017/05/04 06:00 [medline]
AID - S0006-2952(16)30077-6 [pii]
AID - 10.1016/j.bcp.2016.05.004 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2016 Jun 15;110-111:25-36. doi: 10.1016/j.bcp.2016.05.004. 
      Epub 2016 May 12.