Pregnancy test not pregnant
Pregnancy test not pregnant

A single gene, called GSNOR, may underlie many of the complications associated with preeclampsia, a life-threatening condition affecting pregnant women. These findings could lead to new diagnostics and treatments, as well as supporting continuing research.

The study was published this week in the Journal of the American Heart Association.  It was led by Shathiyah Kulandavelu, Ph.D., and Joshua Hare, M.D., of the University of Miami Miller School of Medicine.

“Medicine has made little to no progress in understanding and treating preeclampsia, and that is reflected in high mortality and complication rate among mothers and newborns,” said Hare, principal investigator on the study and director of the Miller School’s Interdisciplinary Stem Cell Institute. “Now, we have discovered an animal model for the syndrome, which is already providing new information into how we might treat it.”

The model has a preeclampsia phenotype, including hypertension, proteinuria, renal pathology, cardiac concentric hypertrophy, decreased placental vascularization, and fetal growth retardation.

Preeclampsia is one of the most common complications in pregnancy and being hotly researched. It causes high blood pressure in mothers-to-be, typically in their third trimester, and in some cases generates organ damage, driving higher mortality in mothers and babies, as well as premature births. In addition, while some women fully recover, others face elevated cardiovascular risks for years after their pregnancies.

This study found that at least one potential cause is a problem in the GSNOR gene. GNOR, S‐nitrosoglutathione reductase (GSNOR−⁄−), is a denitrosylase regulating protein.

Many enzymes undergo nitrosylation, during which a nitric oxide (NO) molecule is attached to the enzyme, increasing its activity. GSNOR removes NO molecules from these enzymes, returning them to a less active state.

GSNOR performs this function on many enzymes, giving it a major impact on cell biology. As a result, when defects in the gene impair GSNOR function, or eliminate the protein entirely, widespread increases in nitrosylation can drive high blood pressure and other preeclampsia-associated effects.

Using a GSNOR-deficient mouse model has given the researchers a new tool to investigate the disease, identify biomarkers and test possible treatments.

To help validate the GSNOR link, the team collected human placentas from preeclampsia patients at UM/Jackson Memorial Hospital. Further analysis showed these women experienced GSNOR loss, confirming the mechanism is important. The team is continuing to study these placentas to identify biomarkers that could inform treatment and delineate the mechanisms that may be driving increased mortality in Black and other communities.

“Hispanic and African American populations have increased incidence of preeclampsia,” said Kulandavelu, assistant research professor in the Department of Pediatrics and first author on the paper. “This has been well-established, but we don’t really know why. Our goal now is to analyze some of the placentas we’ve collected and find markers that could identify women who may be predisposed to preeclampsia and start early treatment.”

“When we look at preeclampsia, we’re finding there are many different subtypes,” added Kulandavelu. “So there could be women with a variety of causes, including increased inflammation, oxidative stress or a genetic disorder, as well as problems with nitrosylation.”

While a defective GSNOR gene may be just one of several potential mechanisms causing preeclampsia, the researchers say that identifying this issue and developing the first robust animal model for the disease is an important step towards better care.

“In one fell swoop, we took away two or three layers of the onion and provided major insights into preeclampsia’s causes, as well as a potential treatment,” said Hare. “That doesn’t mean it’s the only thing going wrong, but it does provide critical information for a pathway that is playing a major role in at least some women.”

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