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Prenatal Nicotine Exposure Raises Male Blood Pressure via FTO-Mediated NOX2/ROS Signaling

Background: Cigarette smoking/nicotine exposure in pregnancy shows an increased risk of hypertension in offspring, but the mechanisms are unclear. This study tested the hypothesis that m6A RNA hypomethylation epigenetically regulates vascular NOX (NADPH oxidase) and reactive oxygen species production, contributing to the fetal programming of a hypertensive phenotype in nicotine-exposed offspring.

Methods: Pregnant rats were exposed to episodic chronic intermittent nicotine aerosol (CINA) or saline aerosol control from gestational day 4 to day 21, and experiments were performed in 6-month-old adult offspring.

Results: Antenatal CINA exposure augmented angiotensin II-stimulated blood pressure response in male, but not female offspring. Moreover, CINA increased vascular NOX2 expression and superoxide production exclusively in male offspring. Inhibition of NOX2 with gp91ds-tat, both ex vivo and in vivo, mitigated the CINA-induced elevation in superoxide production and blood pressure response. Notably, CINA enhanced the expression of vascular m6A demethylase FTO (fat mass and obesity-associated protein), while reducing the total vascular m6A abundance and specific m6A methylation of the NOX2 gene. Additionally, ex vivo inhibition of FTO with FB23-2 attenuated CINA-induced increases in vascular NOX2 expression. In vitro experiments using human umbilical vein endothelial cells demonstrated that nicotine dose-dependently upregulated FTO and NOX2 protein abundance, which were reversed by treatment with the FTO inhibitor FB23-2 or FTO knockdown using siRNAs.

Conclusions: This study uncovers a new mechanism: m6A demethylase FTO-mediated epigenetic upregulation of vascular NOX2 signaling in CINA-induced hypertensive phenotype. This insight could lead to a therapeutic target for preventing and treating developmental hypertension programming.

 

Comments:

This study explores the impact of nicotine exposure during pregnancy on offspring, specifically regarding hypertension risk and vascular health. It suggests that nicotine exposure might increase the risk of hypertension in male offspring by affecting the expression of certain genes involved in reactive oxygen species production in blood vessels.

The study's key findings include:

1. **Increased Blood Pressure Response:** Male offspring exposed to nicotine in utero showed an amplified response to angiotensin II, a hormone involved in blood pressure regulation.

2. **Elevated NOX2 Expression and Superoxide Production:** Nicotine exposure led to increased expression of NOX2 (NADPH oxidase) and higher superoxide production in the vasculature, but this effect was observed exclusively in male offspring.

3. **Role of m6A Methylation:** Nicotine exposure affected the m6A methylation process in the vasculature. It increased the expression of the FTO enzyme responsible for m6A demethylation while reducing the overall m6A methylation and specific methylation of the NOX2 gene.

4. **FTO Inhibition's Effect:** Inhibition of FTO (with FB23-2) lessened the increased expression of NOX2 caused by nicotine exposure, suggesting a potential link between FTO-mediated m6A demethylation and NOX2 expression.

5. **In Vitro Validation:** Experiments with human cells demonstrated that nicotine increased FTO and NOX2 expression, which could be reversed by inhibiting FTO or reducing FTO levels using specific methods.

These findings suggest a potential mechanism by which nicotine exposure during pregnancy could affect the epigenetic regulation of genes involved in hypertension programming in male offspring.

The identification of the FTO-mediated epigenetic pathway sheds light on a potential therapeutic target for preventing or treating hypertension resulting from developmental exposure to nicotine. However, further research is needed to validate these findings and explore their implications for developing interventions to mitigate the long-term health effects of prenatal nicotine exposure.

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P1213 gp91ds-tat gp91ds-tat, a peptide inhibitor for NADPH oxidase assembly, is composed of gp91phox sequence linked to the human immunodeficiency virus-tat peptide. The tat sequence facilitates the entry of this peptide into cells.

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