Hydrogen sulfide releasing molecule MZe786 inhibits soluble Flt-1 and prevents preeclampsia in a refined RUPP mouse model

Abstract

An imbalance in angiogenic growth factors and poor utero-placental perfusion are strongly associated with preeclampsia. The reduced utero-placental perfusion (RUPP) model that mimics insufficient placental perfusion is used to study preeclampsia. The aim of this study was to develop a refined RUPP model in C57Bl/6 J mice to test the efficacy of MZe786 as a potential inhibitor of soluble Flt-1 for preeclampsia therapy. Murine RUPP (mRUPP) was induced through bilateral ligation of the ovarian arteries at E11.5 that resulted in typical preeclampsia symptoms including increase in mean arterial pressure (MAP), kidney injury and elevated soluble Flt-1 (sFlt-1) levels in the maternal plasma and amniotic fluid. The murine RUPP kidneys showed tubular and glomerular damage along with increased oxidative stress characterised by increased nitrotyrosine staining. The mRUPP displayed abnormal placental vascular histology, reduced expression of placental cystathionine γ-lyase (CSE), the hydrogen sulfide (H 2S) producing enzyme, and resulted in adverse fetal outcomes (FGR). Importantly, oral administration of hydrogen sulfide (H 2S)-releasing compound MZe786 from E11.5 to E17.5 successfully prevented the development of preeclampsia. Specifically, MZe786 treatment reduced maternal MAP and kidney nitrotyrosine staining and improved fetal outcome. The circulation levels of sFlt-1 were dramatically decreased in MZe786 treated animals implying that H 2S released from MZe786 offered protection by inhibiting sFlt-1 levels. MZe786 prevent preeclampsia and warrant a rapid move to randomised control clinical trial.

Publication DOI: https://doi.org/10.1016/j.redox.2020.101814
Divisions: College of Health & Life Sciences > Aston Medical School
College of Health & Life Sciences > Aston Medical School > Translational Medicine Research Group (TMRG)
College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine
College of Health & Life Sciences > School of Biosciences
Additional Information: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) Funding: This work was supported in part by grants from the British Heart Foundation (FS/15/72/31676) and Medical Research Council (G0700288) to AA and grants (FP-51-42 and IFPHI-058-130-2020) from the Deanship of Scientific Affairs, King Abdulaziz University, Jeddah to FAA and AA.
Uncontrolled Keywords: Hydrogen sulfide,Mouse model,Nitrosative stress,Preeclampsia,Soluble Flt-1,Organic Chemistry,Clinical Biochemistry
Full Text Link:
Related URLs: https://www.sci ... 0193?via%3Dihub (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2021-01
Published Online Date: 2020-11-28
Accepted Date: 2020-11-25
Authors: Saif, Jaimy
Ahmad, Shakil (ORCID Profile 0000-0002-9294-0475)
Rezai, Homira
Litvinova, Karina (ORCID Profile 0000-0003-1110-8589)
Sparatore, Anna
Alzahrani, Faisal A.
Wang, Keqing (ORCID Profile 0000-0001-6239-6344)
Ahmed, Asif

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