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Published on: January 26, 2024
Placental Nkx2-5 and target gene expression in early-onset and severe preeclampsia
Elena R Rivers1, Anthony J Horton, Angela F Hawk
1Department of Pediatrics, Children's Hospital, Medical University of South Carolina , Charleston, SC , USA .
Insights
Abnormal expression of the cardiovascular developmental transcription factor Nkx2-5 is linked to early-onset severe preeclampsia (EOSPE). This suggests Nkx2-5 influences EOSPE severity and racial disparities via its target gene Sam68 and sFlt-1 expression.
Area of Science:
- Reproductive biology
- Cardiovascular development
- Genetics
Background:
- Preeclampsia (PE) is a major cause of maternal and neonatal morbidity.
- The underlying mechanisms of PE, particularly early-onset severe preeclampsia (EOSPE), remain poorly understood.
- Risk factors and etiology require further investigation.
Purpose of the Study:
- To investigate the association between abnormal expression of the cardiovascular developmental transcription factor Nkx2-5 and EOSPE.
- To explore the potential role of Nkx2-5 in the pathogenesis and severity of EOSPE.
Main Methods:
- Quantitative PCR (qPCR) and immunohistochemical assays were used to examine Nkx2-5 and target gene expression in placental tissues from EOSPE and control groups.
- Mechanistic hypotheses were tested in cultured cells using shRNA knockdown, qPCR, and western blot analysis.
- Expression levels of Nkx2-5, Sam68, and sFlt-1 were analyzed.
Main Results:
- Nkx2-5 expression showed a racially disparate pattern (Caucasians > African Americans) in a subset of EOSPE placentae.
- Nkx2-5 mRNA levels strongly correlated with sFlt-1 and Sam68 mRNA levels, also in a racially disparate manner.
- Knockdown of Sam68 in cultured cells altered sFlt-1 mRNA isoform generation, supporting a mechanism where Nkx2-5 upregulates Sam68 to increase sFlt-1 expression.
- Elevated expression of other Nkx2-5 targets involved in metabolic stress response was observed in EOSPE, with racial disparities.
Conclusions:
- Nkx2-5 expression and its target genes may contribute to the development and racially disparate severity of EOSPE.
- These findings suggest a mechanistically distinct subclass of EOSPE associated with Nkx2-5 dysregulation.
- Nkx2-5 represents a potential factor influencing PE pathogenesis and outcomes.
Objective:
Preeclampsia (PE) affects 2-8% of pregnancies worldwide and is a significant source of maternal and neonatal morbidity and mortality. However, the mechanisms underlying PE are poorly understood and major questions regarding etiology and risk factors remain to be addressed. Our objective was to examine whether abnormal expression of the cardiovascular developmental transcription factor, Nkx2-5, was associated with early onset and severe preeclampsia (EOSPE).
Methods:
Using qPCR and immunohistochemical assay, we examined expression of Nkx2-5 and target gene expression in EOSPE and control placental tissue. We tested resulting mechanistic hypotheses in cultured cells using shRNA knockdown, qPCR, and western blot.
Results:
Nkx2-5 is highly expressed in racially disparate fashion (Caucasians > African Americans) in a subset of early EOSPE placentae. Nkx2-5 mRNA expression is highly correlated (Caucasians > African Americans) to mRNA expression of the preeclampsia marker sFlt-1, and of the Nkx2-5 target and RNA splicing factor, Sam68. Knockdown of Sam68 expression in cultured cells significantly impacts sFlt-1 mRNA isoform generation in vitro, supporting a mechanistic hypothesis that Nkx2-5 impacts EOSPE severity in a subset of patients via upregulation of Sam68 to increase sFlt-1 expression. Expression of additional Nkx2-5 targets potentially regulating metabolic stress response is also elevated in a racially disparate fashion in EOSPE.
Conclusions:
Expression of Nkx2-5 and its target genes may directly influence the genesis and racially disparate severity, and define a mechanistically distinct subclass of EOSPE.
