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：
10533743
负责人：
Sanjay Srivastava
金额：
$ 72.02万
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 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10533743
关键词：
Acetaldehyde Acrolein Aerosols Affect Aldehydes Animal Experiments Animal Model Aorta 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 Electronics 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 Macrophage Activation Matrix Metalloproteinases Measures Mediating MicroRNAs Molecular Mus Myeloid Cells Myocardial Infarction Nature Necrosis Nicotine Nitrosamines Oral Pathway interactions Persons 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 aerosolized air filter alpha-bungarotoxin receptor atherogenesis atherosclerosis risk chronic inflammatory disease cigarette smoke cigarette smoking cigarillos combustible cigarette combustion product cytokine electronic hookah electronic liquid feeding heart disease risk hookah insight mortality risk nicotine vapor 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.

尼古丁是各种烟草产品中的绝对毒性，包括香烟烟雾，无烟烟草，雪茄，雪茄和水烟。烟草产品的使用增加了风险用于动脉粥样硬化。尽管传统香烟的用法在最后一次悄悄地下降了三十年来，使用新的和新兴的烟草产品以及电子尼古丁的传递系统（末端），例如电子烟（E-cig），E-Hookah和电子烟的增加指数。末端将一种称为“电子液体”的溶液雾化（通常是组合丙烯，PG和蔬菜甘油，VG），其中含有少量的尼古丁。虽然几种组合产品和毒素，例如CO和烟草特异性亚硝胺在末端不可检测，包括短链有毒醛在内的羰基（丙烯醛，甲醛，乙醛等在电子烟的气溶胶中已检测到水平在烟草中发现。我们的初步数据表明，暴露于电子烟或其成分，例如丙烯醛和尼古丁（口腔暴露）诱导巨噬细胞激活（细胞因子形成， MMP激活和凋亡）和加剧动脉粥样硬化。相反，淬火内源性醛通过喂食内源性二肽 - carnosine（β-ala-His）或巨噬细胞中过度表达的肌肽合酶可防止动脉粥样硬化。我们的初步研究还表明，长期暴露于电子烟，尼古丁和丙烯醛会增加表达动脉粥样硬化小鼠主动脉中的微RNA-21（miR-21）；丙烯醛和尼古丁诱导 miR-21在培养中的巨噬细胞中，可以认为是对巨噬细胞的自适应反应激活。基于这些观察结果，我们假设miR-21降低了终端诱导通过防止终源性醛和尼古丁的巨噬细胞激活巨噬细胞来进行动脉粥样硬化。为了检验该假设，我们将1）检查电子烟对动脉粥样硬化的影响。在LDL接收器中 - 暴露于过滤空气的无效小鼠，丙烯乙二醇比例不同：蔬菜甘油（VG），PG：VG +尼古丁和Juul特异性电子液体，我们将量化时间，剂量 - 和性别 - 动脉粥样硬化病变形成的依赖性变化。我们将研究如何结束组件影响斑块组成，性质和稳定性； 2）描述终源性醛的动脉粥样硬化贡献。我们将检查E-是否淬灭液体和终端醛通过口服肉肽或巨噬细胞特异性的醛肌肽合酶的过表达可防止巨噬细胞激活和动脉粥样硬化和这些过程如何由miR-21调节？ 3）阐明末端的动脉粥样硬化尼古丁。我们将探测末端如何激活巨噬细胞α7NACHR，以及巨噬细胞特异性 α7NACHR的缺乏会影响终端诱导的巨噬细胞激活和动脉粥样硬化。我们将还要检查miR-21如何调节这些过程。总体而言，拟议的研究将建立末端引起的动脉粥样硬化的新型动物模型，并描绘了底下化学物质的动物模型，细胞和毒性的分子机制。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tobacco Smoke and Endothelial Dysfunction: Role of Aldehydes?

DOI：
10.1007/s11906-020-01085-7
发表时间：
2020-08-28
期刊：
Current hypertension reports
影响因子：
5.6
作者：
Lynch J;Jin L;Richardson A;Conklin DJ
通讯作者：
Conklin DJ

How Irritating! Electronic Cigarettes Not "95% Safer" Than Combustible Cigarettes: Recent Mechanistic Insights Into Endothelial Dysfunction.

DOI：
10.1161/atvbaha.122.318468
发表时间：
2022-11
期刊：
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
影响因子：
8.7
作者：
Conklin, Daniel J.
通讯作者：
Conklin, Daniel J.

Acrolein but not its metabolite, 3-Hydroxypropylmercapturic acid (3HPMA), activates vascular transient receptor potential Ankyrin-1 (TRPA1): Physiological to toxicological implications.

DOI：
10.1016/j.taap.2021.115647
发表时间：
2021-09-01
期刊：
Toxicology and applied pharmacology
影响因子：
3.8
作者：
Jin L;Lorkiewicz P;Xie Z;Bhatnagar A;Srivastava S;Conklin DJ
通讯作者：
Conklin DJ

Chronic Benzene Exposure Aggravates Pressure Overload-Induced Cardiac Dysfunction.

慢性苯暴露会加重压力过载引起的心脏功能障碍。

DOI：
10.1093/toxsci/kfab125
发表时间：
2021
期刊：
Toxicological sciences : an official journal of the Society of Toxicology
影响因子：
0
作者：
Zelko,IgorN;Dassanayaka,Sujith;Malovichko,MarinaV;Howard,CaitlinM;Garrett,LaurenF;Uchida,Shizuka;Brittian,KennethR;Conklin,DanielJ;Jones,StevenP;Srivastava,Sanjay
通讯作者：
Srivastava,Sanjay

Composition of aerosols from thermal degradation of flavors used in ENDS and tobacco products.