Enzyme Deficiency Linked to Preeclampsia

NEW YORK (Reuters Health) – Both preeclamptic mice and human placentas from women with preeclampsia show a deficiency of S-nitrosoglutathione reductase (GSNOR), suggesting that the deficiency underlies the condition, researchers have found.

Notably, in mice, ascorbic acid ameliorated most of the symptoms.

“It was surprising that a mutation in a single gene, GSNOR, can cause many of the complications associated with preeclampsia,” Dr. Shathiyah Kulandavelu of the Miller School of Medicine, University of Miami told Reuters Health by email.

“Preeclampsia is a multisystemic/multifactorial disease, and based on the heterogeneity of the clinical presentation, there may be different subtypes,” she said. “Therefore, identifying women showing dysregulation in nitrosylation and/or altered GSNOR activity levels may be an ideal target subpopulation for treatment with vitamin C or another antioxidant, permitting for a precision medicine approach for future clinical trials.”

The disorder is characterized by “an increase in nitrosylated proteins and reactive oxygen species, suggesting a pathophysiologic role for dysregulation in nitrosylation and nitrosative stress,” Dr. Kulandavelu and colleagues note in the Journal of the American Heart Association.

The team showed that mice lacking S-nitrosoglutathione reductase (GSNOR−⁄−), a denitrosylase that regulates protein S-nitrosylation, have a preeclampsia phenotype, including hypertension, proteinuria, renal pathology, cardiac concentric hypertrophy, decreased placental vascularization, and fetal growth retardation.

In such mice, reactive oxygen species, nitric oxide, and peroxynitrite levels are elevated and, notably, mass spectrometry showed elevated placental S-nitrosylated amino acid residues.

Further investigation showed that ascorbate reverses the phenotype, except for fetal weight, and reduces the difference in the S-nitrosoproteome.

The team then studied human preeclamptic placentas and found decreased GSNOR activity and increased nitrosative stress, similar to the mouse model.

Summing up, the authors state, “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…insights and therapeutic implications for preeclampsia.”

Dr. Kulandavelu said the team’s next research steps will include studying the placentas collected from preeclamptic mothers to identify biomarkers that could inform treatment and better mechanistic understanding of what may be driving the increased mortality and complications in both the mother and newborn.

“Furthermore,” she said, “emerging data suggest that preeclamptic mothers and babies born to preeclamptic mothers are predisposed to future cardiovascular and renal disease. Therefore, the next step will be to follow these mothers and newborns later in life to examine whether they show early signs of cardiovascular and renal disease.”

Dr. Lara Kovell, Director, Pregnancy and Heart Disease Clinic at the University of Massachusetts Chan Medical School, commented in an email to Reuters Health, “This is an exciting study that helps to shed light on the pathology of preeclampsia”

Regarding specific findings, she noted, “Antioxidant treatment rescued preeclampsia phenotypes in the mouse model. However, prior human studies on antioxidants have not ended up helping to prevent preeclampsia. The authors suggest that is because of multiple preeclamptic phenotypes, with likely more than one potential cause. Eventually, precision medicine should help to determine who would benefit the most from these antioxidant treatments.”

“Another concern is that in the mouse model, fetal weight did not improve in the GSNOR knockout mice treated with ascorbate,” she said. “So, while the maternal condition improved, the infant outcomes were not uniformly improved.”

Further, she said, “nearly all of the human placentas came from Non-Hispanic Black participants. It would also be meaningful to have a comparator group of non-Black women with preeclampsia, to see if lower GSNOR activity is a common pathway for preeclampsia across women of different races.”

“The human placentas from women with preeclampsia were at mean gestational age of 36 weeks,” she added. “It would also be interesting to see if early-onset preeclampsia (prior to 34 weeks) had more severely reduced GSNOR activity.”

SOURCE: https://bit.ly/3Hw4cAt Journal of the American Heart Association, online February 22, 2022.

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