Maternal inhaled nicotine leads to aberrant development of hypertensive phenotype

母亲吸入尼古丁导致高血压表型异常发展

• 批准号: 9404487
• 负责人: XUESI Max SHAO
• 金额: $ 45.68万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9404487
• 关键词: Adult; Adult Children; Aerosols; Affect; Alveolar; Animal Model; Animals; Biological Markers; Blood; Blood Circulation; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Child; Chronic; Cigarette; Circadian Rhythms; Clinic; Collaborations; DNA Methylation; DNA Modification Methylases; Data; Development; Diagnostic; Disease; Dose; Drug Kinetics; Electronic cigarette; Environmental Exposure; Epigenetic Process; Etiology; Exposure to; Female; Fetus; Functional disorder; Gender; Gene Expression; Generations; Genes; Genetic Transcription; Human; Hypertension; Inhalation; Islets of Langerhans; Kinetics; Legal patent; Life; Link; Lung; Maternal Health; Mediating; Messenger RNA; Methods; Methylation; Modeling; Molecular; Mothers; NADPH Oxidase; Nicotine; Outcome; Oxidative Stress; Peptides; Perinatal; Pharmacology; Phenotype; Positioning Attribute; Pre-Eclampsia; Pregnancy; Pregnant Women; Preventive; Production; Public Health; Rattus; Reactive Oxygen Species; Research; Risk; Risk Factors; Rodent; Route; Signal Transduction; Small Interfering RNA; Smoke; Smoker; Smoking; Technology; Testing; Tobacco; Universities; Up-Regulation; Vascular Diseases; Venous; Woman; antenatal; cardiovascular disorder risk; cigarette smoking; diabetic; epidemiology study; epigenetic marker; fetal; fetal programming; in utero; in vivo; innovation; male; neonate; new therapeutic target; nicotine abuse; nicotine exposure; nicotine inhalation; nicotine use; nicotine use in pregnancy; novel; offspring; oxidative damage; postnatal; pregnant; prenatal exposure; programs; promoter; protein expression; response; tobacco use in pregnancy; transcriptome

Inhaled nicotine abuse either from tobacco cigarette or e-cigarette smoking is one of the most important risk factors in development of cardiovascular disease. Recent studies in women and animal models indicate that cigarette smoking or nicotine use by mothers during pregnancy increases the risk of hypertension and cardiovascular diseases in offspring. Oxidative stress has been implicated in the etiology of many diseases with substantial public health impact including chronic cardiovascular disorders and preeclampsia. Our recent studies in pregnant rats have demonstrated that perinatal nicotine exposure causes a development of vascular dysfunctional phenotype associated with an increased vascular specific NADPH oxidase (NOX2) gene expression and reactive oxygen species (ROS) production in adult offspring. However, the molecular mechanisms underlying nicotine-mediated programming of vascular oxidative stress are unclear. In addition, whether the heightened oxidative stress contributes to development of hypertensive phenotype remains undetermined. Recently, our research team has developed a non-invasive method delivering nicotine to rodents through inhalation with lung alveolar region-targeted aerosol technology (patent No. 61/418,304) that enables rapid delivery of adequate and controllable amount of nicotine into the circulation. This method closely resembles the route and both the arterial and venous blood nicotine kinetics of smoking a cigarette in human, and induces dose-dependent pharmacological effects in rodents. Our previous data show that chronic intermittent nicotine aerosol treatment (CINA) to rats produces circadian blood pharmacokinetics resembling chronic smokers. Therefore, in this proposed studies we will use the unique CINA pregnant rat model to test the central hypothesis that antenatal exposure to maternal inhaled nicotine programs vascular oxidative stress via epigenetic up-regulation of NOX2 gene, resulting in a hypertensive phenotype in offspring. Our working Specific Aim 1 will determine nicotine pharmacokinetics (PK) in CINA inhaled pregnant rats with our novel alveolar region-targeted aerosol technology and adjust the parameters of aerosol generation/exposure to simulate the PK of human chronic smokers. Specific Aim 2 will test the hypothesis that antenatal inhaled nicotine programs of vascular oxidative stress via epigenetic up-regulation of NOX2 expression. Specific Aim 3 will test the hypothesis that antenatal inhaled nicotine causes a development of hypertensive phenotype which is regulated by NOX2-related ROS signaling. The proposed studies will resolve whether maternal inhaled nicotine during pregnancy programs fetal oxidative stress and contributes to the development of hypertensive phenotype in adulthood. Innovative approaches in these studies provide the opportunity to identify epigenetic biomarkers during early life that have diagnostic and preventive value to the consequences of in utero adverse environmental exposure-induced cardiovascular disease in adulthood.

通过吸烟或电子烟吸入尼古丁滥用是最重要的原因之一 心血管疾病发展的危险因素。最近对女性和动物模型的研究表明 母亲在怀孕期间吸烟或使用尼古丁会增加患高血压的风险 后代心血管疾病。氧化应激与许多疾病的病因有关 对公共健康产生重大影响，包括慢性心血管疾病和先兆子痫。我们最近的 对怀孕大鼠的研究表明，围产期接触尼古丁会导致血管发育 与血管特异性 NADPH 氧化酶 (NOX2) 基因增加相关的功能障碍表型 成年后代的表达和活性氧（ROS）的产生。然而，分子 尼古丁介导的血管氧化应激程序的机制尚不清楚。此外， 氧化应激加剧是否会导致高血压表型的发展仍然存在 未确定。最近，我们的研究团队开发了一种非侵入性方法，将尼古丁输送到 啮齿动物通过吸入肺泡区域靶向气雾剂技术（专利号 61/418,304） 能够将足够且可控量的尼古丁快速输送到循环中。这个方法紧密 类似于人类吸烟的途径以及动脉和静脉血液尼古丁动力学， 并在啮齿动物中诱导剂量依赖性药理作用。我们之前的数据显示，慢性 对大鼠进行间歇性尼古丁气雾剂治疗 (CINA) 产生的昼夜血液药代动力学类似于 长期吸烟者。因此，在这项拟议的研究中，我们将使用独特的 CINA 怀孕大鼠模型来测试 中心假设是产前接触母亲吸入尼古丁会导致血管氧化应激 通过NOX2基因的表观遗传上调，导致后代出现高血压表型。我们的工作 具体目标 1 将用我们的新型药物测定 CINA 吸入怀孕大鼠中的尼古丁药代动力学 (PK) 针对肺泡区域的气溶胶技术并调整气溶胶产生/暴露的参数 模拟人类长期吸烟者的PK。具体目标 2 将检验产前吸入的假设 尼古丁通过表观遗传上调 NOX2 表达来调节血管氧化应激。具体目标 3 将检验产前吸入尼古丁导致高血压表型发展的假设 受 NOX2 相关 ROS 信号传导的调节。拟议的研究将解决母亲是否吸入 怀孕期间的尼古丁会影响胎儿的氧化应激并导致高血压的发生 成年后的表型。这些研究中的创新方法提供了识别表观遗传的机会 生命早期的生物标志物，对子宫内不良后果具有诊断和预防价值 环境暴露诱发的成年期心血管疾病。