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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

基本信息

批准号：
10064004
负责人：
XUESI Max SHAO
金额：
$ 43.05万
依托单位：
LOMA LINDA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10064004
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 Clinic Collaborations DNA Methylation DNA Modification Methylases Data Development Diagnostic Disease Dose Drug Kinetics Electronic cigarette Environmental Exposure Epigenetic Process Etiology Exposure to Female Fetal Tissues 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 circadian 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 cigarette smoking prenatal exposure programs promoter protein expression response transcriptome

项目摘要

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.

吸入尼古丁滥用无论是从烟草香烟或电子烟吸烟是最重要的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，心血管疾病。氧化应激与许多疾病的病因有关对公众健康有重大影响，包括慢性心血管疾病和先兆子痫。我们最近对妊娠大鼠的研究表明，围产期尼古丁暴露会导致血管性心脏病的发生，与血管特异性NADPH氧化酶（NOX 2）基因增加相关的功能障碍表型表达和活性氧（ROS）的产生。然而，分子尼古丁介导的血管氧化应激编程的潜在机制尚不清楚。此外，本发明还提供了一种方法，氧化应激的升高是否有助于高血压表型的发展，不确定。最近，我们的研究小组开发了一种非侵入性的方法，啮齿类动物通过吸入肺泡区域靶向气雾剂技术（专利号61/418，304），能够将足够的和可控量的尼古丁快速输送到循环中。这种方法密切类似于人体吸烟的途径以及动脉和静脉血液尼古丁动力学，并在啮齿类动物中诱导剂量依赖性药理作用。我们之前的数据显示，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长期吸烟者。因此，在本研究中，我们将使用独特的CINA妊娠大鼠模型来测试产前暴露于母体吸入的尼古丁程序血管氧化应激的中心假设通过NOX 2基因的表观遗传上调，导致后代的高血压表型。我们的工作具体目标1将确定尼古丁的药代动力学（PK），在CINA吸入妊娠大鼠与我们的新的肺泡区域靶向气溶胶技术，并调整气溶胶生成/暴露的参数，模拟人类慢性吸烟者的PK。具体目标2将检验产前吸入尼古丁通过表观遗传上调NOX 2表达的血管氧化应激程序。具体目标3 将检验产前吸入尼古丁会导致高血压表型发展的假设，受NOX 2相关的ROS信号调节。拟议的研究将解决产妇是否吸入怀孕期间的尼古丁程序胎儿氧化应激，并有助于高血压的发展在成年期表现型。这些研究中的创新方法提供了识别表观遗传的机会早期生命中对子宫内不良后果具有诊断和预防价值的生物标志物成年期环境压力诱发的心血管疾病。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Role of DNA methylation in perinatal nicotine-induced development of heart ischemia-sensitive phenotype in rat offspring.

DOI：
10.18632/oncotarget.20172
发表时间：
2017-09-29
期刊：
Oncotarget
影响因子：
0
作者：
Ke J;Dong N;Wang L;Li Y;Dasgupta C;Zhang L;Xiao D
通讯作者：
Xiao D

Repression of the Glucocorticoid Receptor Aggravates Acute Ischemic Brain Injuries in Adult Mice.

糖皮质激素受体的抑制会加重成年小鼠的急性缺血性脑损伤。

DOI：
10.3390/ijms19082428
发表时间：
2018
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Li,Yong;Huang,Lei;Ma,Qingyi;Concepcion,KatherineR;Song,MinwooA;Zhang,Peng;Fu,Yingjie;Xiao,Daliao;Zhang,Lubo
通讯作者：
Zhang,Lubo

Neonatal Lipopolysaccharide Exposure Gender-Dependently Increases Heart Susceptibility to Ischemia/Reperfusion Injury in Male Rats.