后代
NADPH氧化酶
内分泌学
内科学
尼古丁
基因敲除
P22phox公司
下调和上调
血管紧张素II
医学
氮氧化物4
活性氧
血压
生物
药理学
氧化应激
细胞生物学
怀孕
生物化学
细胞凋亡
遗传学
基因
作者
Bailin Liu,Liang Xia,Yong Li,Shilin Jiang,Wansu Yu,Li Zhang,Xuesi M. Shao,Zhice Xu,Daliao Xiao
出处
期刊:Hypertension
[Ovid Technologies (Wolters Kluwer)]
日期:2023-10-05
被引量:3
标识
DOI:10.1161/hypertensionaha.123.21766
摘要
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.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.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.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.
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