S-Nitrosoglutathione Reductase Deficiency Causes Aberrant Placental S-Nitrosylation and Preeclampsia

Shathiyah Kulandavelu, Raul A. Dulce, Christopher I. Murray, Michael A. Bellio, Julia Fritsch, Rosemeire Kanashiro-Takeuchi, Himanshu Arora, Ellena Paulino, Daniel Soetkamp, Wayne Balkan, Jenny E. Van Eyk, Joshua M. Hare

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Preeclampsia, a leading cause of maternal and fetal mortality and morbidity, is characterized by an increase in S-nitrosylated proteins and reactive oxygen species, suggesting a pathophysiologic role for dysregulation in nitrosylation and nitrosative stress. METHODS AND RESULTS: Here, we show that mice lacking S-nitrosoglutathione reductase (GSNOR−⁄−), a denitrosylase regulating protein S-nitrosylation, exhibit a preeclampsia phenotype, including hypertension, proteinuria, renal pathology, cardiac concentric hypertrophy, decreased placental vascularization, and fetal growth retardation. Reactive oxygen species, NO, and peroxynitrite levels are elevated. Importantly, mass spectrometry reveals elevated placental S-nitrosylated amino acid residues in GSNOR−⁄− mice. Ascorbate reverses the phenotype except for fetal weight, reduces the difference in the S-nitrosoproteome, and identifies a unique set of S-nitrosylated proteins in GSNOR−⁄− mice. Importantly, human preeclamptic placentas exhibit decreased GSNOR activity and increased nitrosative stress. CONCLUSIONS: Therefore, deficiency of GSNOR creates dysregulation of placental S-nitrosylation and preeclampsia in mice, which can be rescued by ascorbate. Coupled with similar findings in human placentas, these findings offer valuable insights and therapeutic implications for preeclampsia.

Original languageEnglish (US)
Article numbere024008
JournalJournal of the American Heart Association
Volume11
Issue number5
DOIs
StatePublished - Mar 1 2022

Keywords

  • NO
  • S-nitrosylation
  • mouse model
  • preeclampsia
  • pregnancy

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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