Hydrogen sulfide releasing molecule MZe786 inhibits soluble Flt-1 and prevents preeclampsia in a refined RUPP mouse model
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 m...
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2021-01-01
|
Series: | Redox Biology |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231720310193 |
id |
doaj-34ceb48821b842baa12fa76230fa7602 |
---|---|
record_format |
Article |
spelling |
doaj-34ceb48821b842baa12fa76230fa76022020-12-31T04:42:00ZengElsevierRedox Biology2213-23172021-01-0138101814Hydrogen sulfide releasing molecule MZe786 inhibits soluble Flt-1 and prevents preeclampsia in a refined RUPP mouse modelJaimy Saif0Shakil Ahmad1Homira Rezai2Karina Litvinova3Anna Sparatore4Faisal A. Alzahrani5Keqing Wang6Asif Ahmed7Mirzyme Therapeutics, Innovation Birmingham Campus, Faraday Wharf, Birmingham, B7 4BB, UK; Aston Medical Research Institute, Aston Medical School, Birmingham, UKMirzyme Therapeutics, Innovation Birmingham Campus, Faraday Wharf, Birmingham, B7 4BB, UK; Aston Medical Research Institute, Aston Medical School, Birmingham, UKMirzyme Therapeutics, Innovation Birmingham Campus, Faraday Wharf, Birmingham, B7 4BB, UKAston Medical Research Institute, Aston Medical School, Birmingham, UKMirzyme Therapeutics, Innovation Birmingham Campus, Faraday Wharf, Birmingham, B7 4BB, UK; Department of Pharmaceutical Science, University of Milan, Milan, ItalyMirzyme Therapeutics, Innovation Birmingham Campus, Faraday Wharf, Birmingham, B7 4BB, UK; King Fahad Center for Medical Research, King Abdulaziz University, Jeddah, Saudi ArabiaMirzyme Therapeutics, Innovation Birmingham Campus, Faraday Wharf, Birmingham, B7 4BB, UK; Aston Medical Research Institute, Aston Medical School, Birmingham, UKMirzyme Therapeutics, Innovation Birmingham Campus, Faraday Wharf, Birmingham, B7 4BB, UK; King Fahad Center for Medical Research, King Abdulaziz University, Jeddah, Saudi Arabia; President's Office, University of Southampton, University Road, Southampton, UK; Corresponding author. Mirzyme Therapeutics Limited, Innovation Birmingham Campus, Faraday Wharf, Holt Street, Birmingham, B7 4BB, United Kingdom,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 (H2S) producing enzyme, and resulted in adverse fetal outcomes (FGR). Importantly, oral administration of hydrogen sulfide (H2S)-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 H2S released from MZe786 offered protection by inhibiting sFlt-1 levels. MZe786 prevent preeclampsia and warrant a rapid move to randomised control clinical trial.http://www.sciencedirect.com/science/article/pii/S2213231720310193PreeclampsiaSoluble Flt-1Hydrogen sulfideNitrosative stressMouse model |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jaimy Saif Shakil Ahmad Homira Rezai Karina Litvinova Anna Sparatore Faisal A. Alzahrani Keqing Wang Asif Ahmed |
spellingShingle |
Jaimy Saif Shakil Ahmad Homira Rezai Karina Litvinova Anna Sparatore Faisal A. Alzahrani Keqing Wang Asif Ahmed Hydrogen sulfide releasing molecule MZe786 inhibits soluble Flt-1 and prevents preeclampsia in a refined RUPP mouse model Redox Biology Preeclampsia Soluble Flt-1 Hydrogen sulfide Nitrosative stress Mouse model |
author_facet |
Jaimy Saif Shakil Ahmad Homira Rezai Karina Litvinova Anna Sparatore Faisal A. Alzahrani Keqing Wang Asif Ahmed |
author_sort |
Jaimy Saif |
title |
Hydrogen sulfide releasing molecule MZe786 inhibits soluble Flt-1 and prevents preeclampsia in a refined RUPP mouse model |
title_short |
Hydrogen sulfide releasing molecule MZe786 inhibits soluble Flt-1 and prevents preeclampsia in a refined RUPP mouse model |
title_full |
Hydrogen sulfide releasing molecule MZe786 inhibits soluble Flt-1 and prevents preeclampsia in a refined RUPP mouse model |
title_fullStr |
Hydrogen sulfide releasing molecule MZe786 inhibits soluble Flt-1 and prevents preeclampsia in a refined RUPP mouse model |
title_full_unstemmed |
Hydrogen sulfide releasing molecule MZe786 inhibits soluble Flt-1 and prevents preeclampsia in a refined RUPP mouse model |
title_sort |
hydrogen sulfide releasing molecule mze786 inhibits soluble flt-1 and prevents preeclampsia in a refined rupp mouse model |
publisher |
Elsevier |
series |
Redox Biology |
issn |
2213-2317 |
publishDate |
2021-01-01 |
description |
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 (H2S) producing enzyme, and resulted in adverse fetal outcomes (FGR). Importantly, oral administration of hydrogen sulfide (H2S)-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 H2S released from MZe786 offered protection by inhibiting sFlt-1 levels. MZe786 prevent preeclampsia and warrant a rapid move to randomised control clinical trial. |
topic |
Preeclampsia Soluble Flt-1 Hydrogen sulfide Nitrosative stress Mouse model |
url |
http://www.sciencedirect.com/science/article/pii/S2213231720310193 |
work_keys_str_mv |
AT jaimysaif hydrogensulfidereleasingmoleculemze786inhibitssolubleflt1andpreventspreeclampsiainarefinedruppmousemodel AT shakilahmad hydrogensulfidereleasingmoleculemze786inhibitssolubleflt1andpreventspreeclampsiainarefinedruppmousemodel AT homirarezai hydrogensulfidereleasingmoleculemze786inhibitssolubleflt1andpreventspreeclampsiainarefinedruppmousemodel AT karinalitvinova hydrogensulfidereleasingmoleculemze786inhibitssolubleflt1andpreventspreeclampsiainarefinedruppmousemodel AT annasparatore hydrogensulfidereleasingmoleculemze786inhibitssolubleflt1andpreventspreeclampsiainarefinedruppmousemodel AT faisalaalzahrani hydrogensulfidereleasingmoleculemze786inhibitssolubleflt1andpreventspreeclampsiainarefinedruppmousemodel AT keqingwang hydrogensulfidereleasingmoleculemze786inhibitssolubleflt1andpreventspreeclampsiainarefinedruppmousemodel AT asifahmed hydrogensulfidereleasingmoleculemze786inhibitssolubleflt1andpreventspreeclampsiainarefinedruppmousemodel |
_version_ |
1724365064481275904 |