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

Jaimy Saif, Shakil Ahmad, Homira Rezai, Karina Litvinova, Anna Sparatore, Faisal A. Alzahrani, Keqing Wang, Asif Ahmed

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number101814
JournalRedox Biology
Volume38
Early online date28 Nov 2020
DOIs
Publication statusPublished - Jan 2021

Bibliographical note

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.

Keywords

  • Hydrogen sulfide
  • Mouse model
  • Nitrosative stress
  • Preeclampsia
  • Soluble Flt-1

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