PMID- 30885203
OWN - NLM
STAT- MEDLINE
DCOM- 20190423
LR  - 20200225
IS  - 1475-2840 (Electronic)
IS  - 1475-2840 (Linking)
VI  - 18
IP  - 1
DP  - 2019 Mar 18
TI  - Altered bioavailability of epoxyeicosatrienoic acids is associated with conduit 
      artery endothelial dysfunction in type 2 diabetic patients.
PG  - 35
LID - 10.1186/s12933-019-0843-z [doi]
LID - 35
AB  - BACKGROUND: This pathophysiological study addressed the hypothesis that soluble 
      epoxide hydrolase (sEH), which metabolizes the vasodilator and anti-inflammatory 
      epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), 
      contributes to conduit artery endothelial dysfunction in type 2 diabetes. METHODS 
      AND RESULTS: Radial artery endothelium-dependent flow-mediated dilatation in 
      response to hand skin heating was reduced in essential hypertensive patients 
      (n = 9) and type 2 diabetic subjects with (n = 19) or without hypertension 
      (n = 10) compared to healthy subjects (n = 36), taking into consideration 
      cardiovascular risk factors, flow stimulus and endothelium-independent dilatation 
      to glyceryl trinitrate. Diabetic patients but not non-diabetic hypertensive 
      subjects displayed elevated whole blood reactive oxygen species levels and loss 
      of NO release during heating, assessed by measuring local plasma nitrite 
      variation. Moreover, plasma levels of EET regioisomers increased during heating 
      in healthy subjects, did not change in hypertensive patients and decreased in 
      diabetic patients. Correlation analysis showed in the overall population that the 
      less NO and EETs bioavailability increases during heating, the more flow-mediated 
      dilatation is reduced. The expression and activity of sEH, measured in isolated 
      peripheral blood mononuclear cells, was elevated in diabetic but not hypertensive 
      patients, leading to increased EETs conversion to DHETs. Finally, hyperglycemic 
      and hyperinsulinemic euglycemic clamps induced a decrease in flow-mediated 
      dilatation in healthy subjects and this was associated with an altered EETs 
      release during heating. CONCLUSIONS: These results demonstrate that an increased 
      EETs degradation by sEH and altered NO bioavailability are associated with 
      conduit artery endothelial dysfunction in type 2 diabetic patients independently 
      from their hypertensive status. The hyperinsulinemic and hyperglycemic state in 
      these patients may contribute to these alterations. Trial registration 
      NCT02311075. Registered December 8, 2014.
FAU - Duflot, Thomas
AU  - Duflot T
AD  - Department of Pharmacology, Rouen University Hospital, 76000, Rouen Cedex, 
      France.
AD  - Normandie Univ, UNIROUEN, INSERM U1096, FHU REMOD-VHF, 76000, Rouen, France.
AD  - Laboratory of Pharmacokinetics, Toxicology and Pharmacogenetics, Rouen University 
      Hospital, 76000, Rouen, France.
FAU - Moreau-Grange, Lucile
AU  - Moreau-Grange L
AD  - Department of Endocrinology, Rouen University Hospital, 76000, Rouen, France.
FAU - Roche, Clothilde
AU  - Roche C
AD  - Normandie Univ, UNIROUEN, INSERM U1096, FHU REMOD-VHF, 76000, Rouen, France.
FAU - Iacob, Michele
AU  - Iacob M
AD  - Department of Pharmacology, Rouen University Hospital, 76000, Rouen Cedex, 
      France.
FAU - Wils, Julien
AU  - Wils J
AD  - Department of Pharmacology, Rouen University Hospital, 76000, Rouen Cedex, 
      France.
AD  - Normandie Univ, UNIROUEN, INSERM U1096, FHU REMOD-VHF, 76000, Rouen, France.
FAU - Remy-Jouet, Isabelle
AU  - Remy-Jouet I
AD  - Normandie Univ, UNIROUEN, INSERM U1096, FHU REMOD-VHF, 76000, Rouen, France.
FAU - Cailleux, Anne-Francoise
AU  - Cailleux AF
AD  - Department of Endocrinology, Rouen University Hospital, 76000, Rouen, France.
FAU - Leuillier, Matthieu
AU  - Leuillier M
AD  - Normandie Univ, UNIROUEN, INSERM U1096, FHU REMOD-VHF, 76000, Rouen, France.
FAU - Renet, Sylvanie
AU  - Renet S
AD  - Normandie Univ, UNIROUEN, INSERM U1096, FHU REMOD-VHF, 76000, Rouen, France.
FAU - Li, Dongyang
AU  - Li D
AD  - Department of Entomology and Nematology, and Comprehensive Cancer Center, 
      University of California, Davis, Davis, CA, 95616, USA.
FAU - Morisseau, Christophe
AU  - Morisseau C
AD  - Department of Entomology and Nematology, and Comprehensive Cancer Center, 
      University of California, Davis, Davis, CA, 95616, USA.
FAU - Lamoureux, Fabien
AU  - Lamoureux F
AD  - Department of Pharmacology, Rouen University Hospital, 76000, Rouen Cedex, 
      France.
AD  - Normandie Univ, UNIROUEN, INSERM U1096, FHU REMOD-VHF, 76000, Rouen, France.
AD  - Laboratory of Pharmacokinetics, Toxicology and Pharmacogenetics, Rouen University 
      Hospital, 76000, Rouen, France.
FAU - Richard, Vincent
AU  - Richard V
AD  - Department of Pharmacology, Rouen University Hospital, 76000, Rouen Cedex, 
      France.
AD  - Normandie Univ, UNIROUEN, INSERM U1096, FHU REMOD-VHF, 76000, Rouen, France.
FAU - Prevost, Gaetan
AU  - Prevost G
AD  - Department of Endocrinology, Rouen University Hospital, 76000, Rouen, France.
AD  - Normandie Univ, UNIROUEN, INSERM U1239, 76000, Rouen, France.
FAU - Joannides, Robinson
AU  - Joannides R
AD  - Department of Pharmacology, Rouen University Hospital, 76000, Rouen Cedex, 
      France.
AD  - Normandie Univ, UNIROUEN, INSERM U1096, FHU REMOD-VHF, 76000, Rouen, France.
AD  - Centre d'Investigation Clinique (CIC)-INSERM 1404, Rouen University Hospital, 
      76000, Rouen, France.
FAU - Bellien, Jeremy
AU  - Bellien J
AUID- ORCID: 0000-0002-0383-2342
AD  - Department of Pharmacology, Rouen University Hospital, 76000, Rouen Cedex, 
      France. jeremy.bellien@chu-rouen.fr.
AD  - Normandie Univ, UNIROUEN, INSERM U1096, FHU REMOD-VHF, 76000, Rouen, France. 
      jeremy.bellien@chu-rouen.fr.
AD  - Centre d'Investigation Clinique (CIC)-INSERM 1404, Rouen University Hospital, 
      76000, Rouen, France. jeremy.bellien@chu-rouen.fr.
LA  - eng
SI  - ClinicalTrials.gov/NCT02311075
GR  - R01 ES002710/ES/NIEHS NIH HHS/United States
GR  - P42 ES004699/ES/NIEHS NIH HHS/United States
GR  - R01 DK103616/DK/NIDDK NIH HHS/United States
GR  - R01 ES002710/NH/NIH HHS/United States
GR  - P42 ES004699/NH/NIH HHS/United States
GR  - R01 DK103616/NH/NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190318
PL  - England
TA  - Cardiovasc Diabetol
JT  - Cardiovascular diabetology
JID - 101147637
RN  - 0 (Biomarkers)
RN  - 0 (Eicosanoids)
RN  - 0 (Nitrites)
RN  - 0 (Vasodilator Agents)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 3.3.2.- (Epoxide Hydrolases)
RN  - EC 3.3.2.10 (EPHX2 protein, human)
RN  - G59M7S0WS3 (Nitroglycerin)
SB  - IM
MH  - Aged
MH  - Biomarkers/blood
MH  - Case-Control Studies
MH  - Diabetes Mellitus, Type 2/*blood/diagnosis/physiopathology
MH  - Diabetic Angiopathies/*blood/diagnosis/physiopathology
MH  - Eicosanoids/*blood
MH  - Epoxide Hydrolases/metabolism
MH  - Essential Hypertension/*blood/diagnosis/physiopathology
MH  - Female
MH  - Humans
MH  - Hyperthermia, Induced
MH  - Male
MH  - Middle Aged
MH  - Nitric Oxide/metabolism
MH  - Nitrites/blood
MH  - Nitroglycerin/administration & dosage
MH  - Radial Artery/drug effects/*metabolism/physiopathology
MH  - *Vasodilation/drug effects
MH  - Vasodilator Agents/administration & dosage
PMC - PMC6423843
OTO - NOTNLM
OT  - Endothelial dysfunction
OT  - Epoxyeicosatrienoic acids
OT  - Soluble epoxide hydrolase
OT  - Type 2 diabetes
COIS- The authors declare that they have no competing interests.
EDAT- 2019/03/20 06:00
MHDA- 2019/04/24 06:00
PMCR- 2019/03/18
CRDT- 2019/03/20 06:00
PHST- 2019/01/09 00:00 [received]
PHST- 2019/03/08 00:00 [accepted]
PHST- 2019/03/20 06:00 [entrez]
PHST- 2019/03/20 06:00 [pubmed]
PHST- 2019/04/24 06:00 [medline]
PHST- 2019/03/18 00:00 [pmc-release]
AID - 10.1186/s12933-019-0843-z [pii]
AID - 843 [pii]
AID - 10.1186/s12933-019-0843-z [doi]
PST - epublish
SO  - Cardiovasc Diabetol. 2019 Mar 18;18(1):35. doi: 10.1186/s12933-019-0843-z.