PMID- 36831332
OWN - NLM
STAT- MEDLINE
DCOM- 20230228
LR  - 20230328
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 12
IP  - 4
DP  - 2023 Feb 20
TI  - Inhibition of Soluble Epoxide Hydrolase Does Not Promote or Aggravate Pulmonary 
      Hypertension in Rats.
LID - 10.3390/cells12040665 [doi]
LID - 665
AB  - Inhibitors of soluble epoxide hydrolase (sEH), which catalyzes the hydrolysis of 
      various natural epoxides to their corresponding diols, present an opportunity for 
      developing oral drugs for a range of human cardiovascular and inflammatory 
      diseases, including, among others, diabetes and neuropathic pain. However, some 
      evidence suggests that their administration may precipitate the development of 
      pulmonary hypertension (PH). We thus evaluated the impact of chronic oral 
      administration of the sEH inhibitor TPPU 
      (N-[1-(1-Oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl]-urea) on 
      hemodynamics, pulmonary vascular reactivity, and remodeling, as well as on right 
      ventricular (RV) dimension and function at baseline and in the Sugen (SU5416) + 
      hypoxia (SuHx) rat model of severe PH. Treatment with TPPU started 5 weeks after 
      SU5416 injection for 3 weeks. No differences regarding the increase in pulmonary 
      vascular resistance, remodeling, and inflammation, nor the abolishment of 
      phenylephrine-induced pulmonary artery constriction, were noted in SuHx rats. In 
      addition, TPPU did not modify the development of RV dysfunction, hypertrophy, and 
      fibrosis in SuHx rats. Similarly, none of these parameters were affected by TPPU 
      in normoxic rats. Complementary in vitro data demonstrated that TPPU reduced the 
      proliferation of cultured human pulmonary artery-smooth muscle cells (PA-SMCs). 
      This study demonstrates that inhibition of sEH does not induce nor aggravate the 
      development of PH and RV dysfunction in SuHx rats. In contrast, a potential 
      beneficial effect against pulmonary artery remodeling in humans is suggested.
FAU - Leuillier, Matthieu
AU  - Leuillier M
AD  - INSERM EnVI UMR 1096, Health Campus, University of Rouen Normandie, F-76000 
      Rouen, France.
FAU - Platel, Valentin
AU  - Platel V
AD  - INSERM EnVI UMR 1096, Health Campus, University of Rouen Normandie, F-76000 
      Rouen, France.
FAU - Tu, Ly
AU  - Tu L
AUID- ORCID: 0000-0003-2336-5099
AD  - INSERM UMR_S 999, Hopital Marie Lannelongue, F-92350 Le Plessis-Robinson, France.
AD  - Faculte de Medecine, Universite Paris-Saclay, F-94276 Le Kremlin-Bicetre, France.
FAU - Feugray, Guillaume
AU  - Feugray G
AD  - INSERM EnVI UMR 1096, Health Campus, University of Rouen Normandie, F-76000 
      Rouen, France.
AD  - Department of General Biochemistry, CHU Rouen, F-76000 Rouen, France.
FAU - Thuillet, Raphael
AU  - Thuillet R
AD  - INSERM UMR_S 999, Hopital Marie Lannelongue, F-92350 Le Plessis-Robinson, France.
AD  - Faculte de Medecine, Universite Paris-Saclay, F-94276 Le Kremlin-Bicetre, France.
FAU - Groussard, Deborah
AU  - Groussard D
AUID- ORCID: 0000-0003-0664-1274
AD  - INSERM EnVI UMR 1096, Health Campus, University of Rouen Normandie, F-76000 
      Rouen, France.
FAU - Messaoudi, Hind
AU  - Messaoudi H
AD  - INSERM EnVI UMR 1096, Health Campus, University of Rouen Normandie, F-76000 
      Rouen, France.
FAU - Ottaviani, Mina
AU  - Ottaviani M
AD  - INSERM UMR_S 999, Hopital Marie Lannelongue, F-92350 Le Plessis-Robinson, France.
AD  - Faculte de Medecine, Universite Paris-Saclay, F-94276 Le Kremlin-Bicetre, France.
FAU - Chelgham, Mustapha
AU  - Chelgham M
AD  - INSERM UMR_S 999, Hopital Marie Lannelongue, F-92350 Le Plessis-Robinson, France.
AD  - Faculte de Medecine, Universite Paris-Saclay, F-94276 Le Kremlin-Bicetre, France.
FAU - Nicol, Lionel
AU  - Nicol L
AUID- ORCID: 0000-0002-7820-4148
AD  - INSERM EnVI UMR 1096, Health Campus, University of Rouen Normandie, F-76000 
      Rouen, France.
FAU - Mulder, Paul
AU  - Mulder P
AD  - INSERM EnVI UMR 1096, Health Campus, University of Rouen Normandie, F-76000 
      Rouen, France.
FAU - Humbert, Marc
AU  - Humbert M
AUID- ORCID: 0000-0003-0703-2892
AD  - INSERM UMR_S 999, Hopital Marie Lannelongue, F-92350 Le Plessis-Robinson, France.
AD  - Faculte de Medecine, Universite Paris-Saclay, F-94276 Le Kremlin-Bicetre, France.
FAU - Richard, Vincent
AU  - Richard V
AD  - INSERM EnVI UMR 1096, Health Campus, University of Rouen Normandie, F-76000 
      Rouen, France.
AD  - Department of Pharmacology, CHU Rouen, F-76000 Rouen, France.
FAU - Morisseau, Christophe
AU  - Morisseau C
AUID- ORCID: 0000-0002-5672-6631
AD  - Department of Entomology and Nematology, UCD Comprehensive Cancer Center, 
      University of California, Davis, CA 95616, USA.
FAU - Brunel, Valery
AU  - Brunel V
AUID- ORCID: 0000-0003-3069-6208
AD  - Department of General Biochemistry, CHU Rouen, F-76000 Rouen, France.
FAU - Duflot, Thomas
AU  - Duflot T
AUID- ORCID: 0000-0002-8730-284X
AD  - INSERM EnVI UMR 1096, Health Campus, University of Rouen Normandie, F-76000 
      Rouen, France.
AD  - Department of Pharmacology, CHU Rouen, F-76000 Rouen, France.
FAU - Guignabert, Christophe
AU  - Guignabert C
AUID- ORCID: 0000-0002-8545-4452
AD  - INSERM UMR_S 999, Hopital Marie Lannelongue, F-92350 Le Plessis-Robinson, France.
AD  - Faculte de Medecine, Universite Paris-Saclay, F-94276 Le Kremlin-Bicetre, France.
FAU - Bellien, Jeremy
AU  - Bellien J
AUID- ORCID: 0000-0002-0383-2342
AD  - INSERM EnVI UMR 1096, Health Campus, University of Rouen Normandie, F-76000 
      Rouen, France.
AD  - Department of Pharmacology, CHU Rouen, F-76000 Rouen, France.
LA  - eng
GR  - R35 ES030443/ES/NIEHS NIH HHS/United States
GR  - P42 ES004699/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230220
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - EC 3.3.2.- (Epoxide Hydrolases)
SB  - IM
MH  - Rats
MH  - Humans
MH  - Animals
MH  - *Hypertension, Pulmonary
MH  - Epoxide Hydrolases/therapeutic use
MH  - Lung
MH  - Heart
MH  - Cells, Cultured
PMC - PMC9954493
OTO - NOTNLM
OT  - epoxyeicosatrienoic acids
OT  - pulmonary arterial hypertension
OT  - right ventricular dysfunction
OT  - soluble epoxide hydrolase
COIS- Over the last three years, C.G. reports grants from Acceleron, Structure 
      Therapeutics (ex-ShouTi), Corteria, and Janssen and grants and personal fees from 
      Merck, outside of the submitted work. M.H. reports grants and personal fees from 
      Acceleron, Structure Therapeutics (ex-ShouTi), Corteria, Bayer, Merck, and 
      Janssen and personal fees from GSK, outside of the submitted work. M.L., V.P., 
      L.T., G.F., R.T., D.G., H.M., M.O., M.C., L.N., P.M., V.R., C.M., V.B., T.D. and 
      J.B. have no conflict of interest to disclose.
EDAT- 2023/02/26 06:00
MHDA- 2023/03/03 06:00
PMCR- 2023/02/20
CRDT- 2023/02/25 01:36
PHST- 2022/11/17 00:00 [received]
PHST- 2023/02/15 00:00 [revised]
PHST- 2023/02/17 00:00 [accepted]
PHST- 2023/02/25 01:36 [entrez]
PHST- 2023/02/26 06:00 [pubmed]
PHST- 2023/03/03 06:00 [medline]
PHST- 2023/02/20 00:00 [pmc-release]
AID - cells12040665 [pii]
AID - cells-12-00665 [pii]
AID - 10.3390/cells12040665 [doi]
PST - epublish
SO  - Cells. 2023 Feb 20;12(4):665. doi: 10.3390/cells12040665.