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

作者全名："Liu, Bailin; Xia, Liang; Li, Yong; Jiang, Siyi; Yu, Wansu; Zhang, Lubo; Shao, Xuesi M.; Xu, Zhice; Xiao, Daliao"

作者地址："[Liu, Bailin; Xia, Liang; Li, Yong; Jiang, Siyi; Yu, Wansu; Zhang, Lubo; Xiao, Daliao] Loma Linda Univ, Lawrence D Longo MD Ctr Perinatal Biol, Dept Basic Sci, Sch Med, Loma Linda, CA 92350 USA; [Liu, Bailin; Xu, Zhice] Jiangnan Univ, Wuxi Matern & Child Hlth Care Hosp, Perinatol Lab, Womens Hosp, Wuxi, Peoples R China; [Xia, Liang] Chongqing Med Univ, Affiliated Hosp 1, Dept Surg Intens Care Unit, Chongqing, Peoples R China; [Shao, Xuesi M.] David Geffen Sch Med UCLA, Dept Neurobiol, Los Angeles, CA USA; [Xu, Zhice] Soochow Univ, Hosp 1, Inst Fetol, Suzhou, Peoples R China"

通信作者："Xiao, DL (通讯作者)，Loma Linda Univ, Lawrence D Longo MD Ctr Perinatal Biol, Dept Basic Sci, Sch Med, Loma Linda, CA 92350 USA."

来源：HYPERTENSION

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001147717700005

JCR分区：Q1

影响因子：8.3

年份：2024

卷号：81

期号：2

开始页：240

结束页：251

文献类型：Article

关键词：aerosols; cardiovascular diseases; methylation; nicotine; phenotype

摘要："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 Ang II (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."

基金机构："National Institutes of Health [HL135623, DA041492, HD088039]; Regents of the University of California, Research Grants Program Office, Tobacco-Related Disease Research Program (TRDRP) [T30FT0936, T32FT4859]"

基金资助正文："This work was supported by National Institutes of Health Grants HL135623, DA041492, and HD088039 (to D. Xiao). This project was partially supported by The Regents of the University of California, Research Grants Program Office, Tobacco-Related Disease Research Program (TRDRP) grants T29IR0437 (to D. Xiao), T30FT0936 (to B. Liu) and T32FT4859 (to Y. Li)."