Atherogenic Mechanisms of Electronic Nicotine Delivery Systems

电子尼古丁输送系统的致动脉粥样硬化机制

基本信息

批准号：
10082463
负责人：
Sanjay Srivastava
金额：
$ 72.11万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10082463
关键词：
Acetaldehyde Acrolein Aerosols Affect Aldehydes Animal Model Animals Apoptosis Arterial Fatty Streak Atherosclerosis Blood Vessels Cardiovascular Diseases Carnosine Cells Cessation of life Characteristics Chemicals Chronic Chronic Disease Cigar Collagen Data Devices Dipeptides Disease Dose Electronic Nicotine Delivery Systems Electronic cigarette Emerging Tobacco Products Endothelium Excision Exposure to Fatty acid glycerol esters Formaldehyde Glycerol Human In Vitro Inflammation Inflammatory JUUL Knockout Mice Lesion Life Low Density Lipoprotein Receptor Macrophage Activation Matrix Metalloproteinases Measures Mediating MicroRNAs Molecular Mus Myeloid Cells Myocardial Infarction Nature Necrosis Nicotine Nitrosamines Oral Pathway interactions Play Process Propylene Glycols Proteins Risk Role Signal Transduction Smoke Smokeless Tobacco Smoker Smoking Smooth Muscle Myocytes Stroke Supplementation Testing Thromboplastin Time Tobacco Tobacco smoke Tobacco use Toxic effect Toxin Trees Untranslated RNA Urine Vegetables adduct air filter alpha-bungarotoxin receptor atherogenesis atherosclerosis risk base chronic inflammatory disease cigarette smoke cigarette smoking cigarillos combustible cigarette combustion product cytokine electronic hookah electronic liquid feeding heart disease risk hookah insight macrophage mortality risk novel overexpression premature prevent recruit response sex tobacco products toxicant vegetable glycerin

项目摘要

Nicotine is an abundant toxicant in various tobacco products including cigarette smoke, smokeless tobacco, cigars, cigarillos, and hookah. The use of tobacco products increase the risk for atherosclerosis. Although usage of conventional cigarette has steadily declined over the last three decades, usage of new and emerging tobacco products and electronic nicotine delivery systems (ENDS) such as electronic cigarettes (e-cig), e-hookah, and e-cigars has increased exponentially. ENDS aerosolize a solution known as an “e-liquid” (typically a combination of propylene glycol, PG, and vegetable glycerol, VG) that contains a small percentage of nicotine. Although several combustion products and toxins such as CO and tobacco-specific nitrosamines are non-detectable in ENDS, carbonyls including short-chain toxic aldehydes (acrolein, formaldehyde, acetaldehyde, etc.) have been detected in e-cig-derived aerosols up to levels found in tobacco smoke. Our preliminary data suggest that exposure to e-cig or its components, such as acrolein and nicotine (oral exposure) induce macrophage activation (cytokine formation, MMP activation, and apoptosis) and exacerbate atherosclerosis. Conversely, quenching of endogenous aldehydes by feeding with the endogenous dipeptide - carnosine (β-ala-his) or overexpressing carnosine synthase in macrophages prevents atherosclerosis. Our preliminary studies also show that chronic exposure to e-cig, nicotine, and acrolein increase the expression of micro RNA-21 (miR-21) in the aortae of atherogenic mice; and acrolein and nicotine induce miR-21 in macrophages in culture, presumable as an adaptive response to macrophage activation. Based on these observations we hypothesize that miR-21 decreases ENDS-induced atherogenesis by preventing macrophage activation by ENDS-derived aldehydes and nicotine. To test this hypothesis, we will 1) Examine the effect of e-cig on atherogenesis. In LDL receptor- null mice exposed to filtered air, varying proportions of propylene glycol (PG):vegetable glycerin (VG), PG:VG + nicotine, and JUUL-specific e-liquids, we will quantify the time-, dose-, and sex- dependent changes in atherosclerotic lesion formation. We will examine how ENDS and their components affect the plaque composition, the nature, and the stability; 2) Delineate the atherogenic contribution of ENDS-derived aldehydes. We will examine whether quenching of e- liquid and ENDS-derived aldehydes by oral feeding with carnosine or macrophage-specific overexpression of carnosine synthase prevents macrophage activation and atherogenesis and how are these processes regulated by miR-21; 3) Elucidate the atherogenicity of ENDSderived nicotine. We will probe how ENDS activate macrophage α7nAChR, and how macrophage-specific deficiency of α7nAChR affects ENDS-induced macrophage activation and atherogenesis. We will also examine how miR-21 regulates these processes. Overall, the proposed studies will establish novel animal models of ENDS-induced atherosclerosis, and delineate the underling chemical, cellular, and molecular mechanisms of toxicity.

尼古丁是各种烟草制品中丰富的有毒物质，包括香烟烟雾、无烟烟草、雪茄、小雪茄和水烟使用烟草制品会增加风险。尽管过去传统香烟的使用量稳步下降。三十年来，新兴烟草产品的使用和电子尼古丁输送电子烟 (e-cig)、电子水烟和电子雪茄等系统 (ENDS) 有所增加 ENDS 以指数方式雾化一种称为“电子液体”的溶液（通常是以下物质的组合）丙二醇 (PG) 和植物甘油 (VG) 含有少量尼古丁。尽管一些燃烧产物和毒素，例如一氧化碳和烟草特有的亚硝胺在 ENDS 中检测不到，羰基化合物包括短链有毒醛（丙烯醛、电子烟气溶胶中检测到的甲醛、乙醛等含量高达我们的初步数据表明，接触电子烟或其成分，例如丙烯醛和尼古丁（口服暴露）会诱导巨噬细胞活化（细胞因子形成， MMP 激活和细胞凋亡）并加剧动脉粥样硬化的离线、猝灭。通过喂食内源性二肽 - 肌肽 (β-ala-his) 或巨噬细胞中过度表达肌肽合酶可预防动脉粥样硬化。研究还表明，长期接触电子烟、尼古丁和丙烯醛会增加表达致动脉粥样硬化小鼠主动脉中的微小 RNA-21 (miR-21) 以及丙烯醛和尼古丁诱导；培养物中巨噬细胞中的 miR-21，可能是对巨噬细胞的适应性反应基于这些观察，我们发现 miR-21 会降低 ENDS 诱导的激活。通过 ENDS 衍生的醛和尼古丁阻止巨噬细胞活化来防止动脉粥样硬化形成。为了检验这一假设，我们将 1) 检查电子烟对 LDL 受体动脉粥样硬化的影响。裸鼠暴露于过滤空气、不同比例的丙二醇（PG）：植物甘油 (VG)、PG:VG+尼古丁、JUUL专用烟油，我们将量化时间、剂量、性别我们将研究ENDS及其形成的相关变化。影响斑块组成、性质和稳定性的成分；2) 描述斑块的组成、性质和稳定性；我们将研究 ENDS 衍生的醛是否会导致动脉粥样硬化。通过口服肌肽或巨噬细胞特异性产生液体和 ENDS 衍生的醛肌肽合酶的过度表达可防止巨噬细胞活化和动脉粥样硬化形成这些过程是如何受 miR-21 调节的；3) 阐明 ENDS 衍生的动脉粥样硬化性我们将探讨 ENDS 如何激活巨噬细胞 α7nAChR，以及巨噬细胞特异性如何。 α7nAChR 缺乏会影响 ENDS 诱导的巨噬细胞活化和动脉粥样硬化形成。总体而言，拟议的研究将确定 miR-21 如何调节这些过程。 ENDS 诱导的动脉粥样硬化的新型动物模型，并描述了底层化学物质，毒性的细胞和分子机制。