E-cigarette aerosol effects on the cardiovascular system in rodents

电子烟气溶胶对啮齿类动物心血管系统的影响

基本信息

批准号：
10227000
负责人：
Eric Richard Gross
金额：
$ 47.43万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-14 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227000
关键词：
Acetaldehyde Acrolein Acute Address Adult Aerosols Affect Alcohols Aldehydes Biochemical Bioenergetics Biological Assay Biological Markers Biology Blood capillaries Calcium Cardiac Myocytes Cardiopulmonary Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cell Death Cell Energetics Cell physiology Cells Cigarette Coupled DNA Damage Diffuse Electrocardiogram Electronic cigarette Endothelial Cells Enzymes Exposure to Formaldehyde Functional disorder Gases Genetic Heart Heart Rate Human Hypoxia Impairment Individual Injury Knock-in Mouse Lead Lung Mass Spectrum Analysis Measures Membrane Potentials Metabolism Mission Mitochondria Monitor Mus Myocardial Infarction National Heart, Lung, and Blood Institute Physiological Poison Primary Cell Cultures Production Protein Chemistry Proteins Pump Research Research Personnel Rodent System Telemetry Testing Time Tobacco Toxic effect Umbilical vein Variant Wild Type Mouse adduct aldehyde dehydrogenases cardiopulmonary system cardiovascular disorder risk cardiovascular effects cell injury e-cigarette aerosols electronic cigarette use genetic variant heart rate variability improved innovation response skills small molecule tool vapor

项目摘要

PROJECT SUMMARY: E-cigarette aerosol contains reactive aldehydes including acetaldehyde, formaldehyde, and acrolein which are highly diffusible into cells. These reactive aldehydes, also found in tobacco cigarettes and alcohol, are known to cause cellular damage that can lead to cardiovascular disease. Further, ~560 million people in the world carry an aldehyde dehydrogenase 2 (ALDH2) genetic variant, ALDH2*2, that severely limits the metabolism of reactive aldehydes such as those present in e-cigarette aerosol. Having an ALDH2*2 variant increases the risk for cardiovascular disease, including cellular damage from a heart attack. However, little is known how the reactive aldehyde levels in e-cigarette aerosol, coupled with this genetic difference present in reactive aldehyde metabolism, effect cardiovascular physiology and cellular function. Here, we will study the effects on the cardiovascular system of e-cigarette aerosol in addition to the individual reactive aldehydes within e-cigarette aerosol using wild type ALDH2 or ALDH2*2 variant knock-in mice. We will do so by (AIM 1) exposing wild type ALDH2 mice and ALDH2*2 knock-in mice to e-cigarette aerosol while monitoring the heart by remote telemetry and quantifying in the heart and lungs the biochemical effects of e- cigarette aerosol exposure. In isolated adult cardiac myocytes (AIM 2), we will determine in wild type ALDH2 and ALDH2*2 knock-in mice how the individual reactive aldehydes in e-cigarette aerosol alter cellular protein adduct formation and cellular function. We will also determine how reactive aldehydes at the levels present in e-cigarette aerosol affect cardiac myocytes subjected to hypoxia-reoxygenation injury. In human umbilical vein endothelial cells and isolated lung primary endothelial cells (AIM3), we will also determine how reactive aldehyde exposure causes changes in protein adduct formation and mitochondrial function that leads to endothelial cell dysfunction. My research team can bring specific skill-sets and unique tools to this field. We will perform studies to uncover how e-cigarette aerosol and the reactive aldehyde present within the aerosol effect the cardiovascular system. In particular, these studies will address the cardiovascular effects of exposure to e-cigarette aerosol and investigate the effects of e-cigarette aerosol exposure on cardiac myocytes and endothelial cells.

项目概要：电子烟气溶胶含有活性醛，包括乙醛、甲醛和丙烯醛，高度扩散至细胞内。这些活性醛也存在于烟草和酒精中，众所周知造成细胞损伤，从而导致心血管疾病。此外，世界上约有 5.6 亿人携带乙醛脱氢酶 2 (ALDH2) 遗传变异体 ALDH2*2，该变异体严重限制了活性醛，例如电子烟气溶胶中存在的醛。拥有 ALDH2*2 变体会增加心血管疾病的风险，包括心脏病发作造成的细胞损伤。然而，很少有人知道如何电子烟气溶胶中的活性醛水平，加上活性醛中存在的遗传差异醛代谢，影响心血管生理和细胞功能。在这里，我们除了研究个人之外，还将研究电子烟气雾剂对心血管系统的影响使用野生型 ALDH2 或 ALDH2*2 变异敲入小鼠研究电子烟气雾剂中的活性醛。我们将通过（目标 1）将野生型 ALDH2 小鼠和 ALDH2*2 敲入小鼠暴露于电子烟气雾剂中，同时通过远程遥测监测心脏并量化电子对心脏和肺部的生化影响香烟气溶胶暴露。在分离的成体心肌细胞 (AIM 2) 中，我们将确定野生型 ALDH2 和 ALDH2*2 敲入小鼠电子烟气溶胶中的单个活性醛如何改变细胞蛋白加合物形成和细胞功能。我们还将确定醛在该水平下的反应性如何电子烟气溶胶会影响遭受缺氧-复氧损伤的心肌细胞。在人脐静脉中内皮细胞和分离的肺原代内皮细胞（AIM3），我们还将确定反应性如何醛暴露会导致蛋白质加合物形成和线粒体功能发生变化，从而导致内皮细胞功能障碍。我的研究团队可以为该领域带来特定的技能和独特的工具。我们将进行研究以揭示电子烟气溶胶和气溶胶中存在的活性醛如何影响心血管系统。特别是，这些研究将解决暴露于电子烟气溶胶和电子烟气溶胶对心血管的影响。研究电子烟气溶胶暴露对心肌细胞和内皮细胞的影响。