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Therapeutic Roles for NAD+ Metabolism in Electronic Cigarettes-Induced Cardiac Dysfunction

NAD 代谢在电子烟引起的心脏功能障碍中的治疗作用

基本信息

批准号：
10217206
负责人：
Jorge Espinoza-Derout
金额：
$ 14.35万
依托单位：
CHARLES R. DREW UNIVERSITY OF MED & SCI
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：
2020-07-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10217206
关键词：
Adipose tissue Adolescent Aerosols Affect Animal Model ApoE knockout mouse Apolipoprotein E Autophagocytosis Basic Science Biogenesis Cardiac Cardiomyopathies Cardiovascular Diseases Cardiovascular Pathology Data Development EFRAC Electronic cigarette Elements Exposure to Faculty Fatty Liver Foundations Generations Genes Genetic Goals Grant Heart Heart failure Hispanic Americans Inflammatory Knock-out Laboratories Left Lipids Lipolysis Maintenance Mediating Medical Metabolic Metabolic Diseases Metabolic syndrome Metabolism Mitochondria Modeling Monitor Mus Myocardial dysfunction Nicotine Nonesterified Fatty Acids Obesity Oxidation-Reduction Oxidative Stress Pharmacology Phenotype Play Production Reactive Oxygen Species Regulation Research Role SIRT1 gene Saline Secure Serum Shortening Fraction Signal Transduction Smoke Smoker Smoking Source Surveys Testing Therapeutic Therapeutic Agents Therapeutic Uses Tobacco use Training United States Ventricular Youth acipimox base cardiovascular effects combustible cigarette design dietary supplements electronic cigarette use electronic cigarette user experience experimental study high risk inhibitor/antagonist lipid biosynthesis mitochondrial DNA mutation mitochondrial dysfunction mouse model nicotinamide-beta-riboside prevent preventable death therapeutic target tool transcriptomics western diet

项目摘要

Espinoza-Derout, Jorge Project Summary: Electronic cigarettes (e-cigarettes) are becoming exceptionally popular worldwide as an alternative to conventional cigarettes, both in smokers and people who have never smoked. To study the cardiac effect of e- cigarettes, I used ApoE knockout (ApoE KO) mice, the most commonly used murine model to study the cardiovascular effects of conventional cigarettes. ApoE KO miceon a western diet (WD) were exposed to saline, e-cigarettes without nicotine (e-cigarettes (0%)) and e-cigarettes with 2.4% nicotine (e-cigarettes (2.4%)) aerosol for 12 weeks. Our preliminary data shows that mice exposed to e-cigarettes (2.4%) have increased levels of serum FFA in comparison with Saline and e-cigarettes (0%). Additionally, e-cigarettes (2.4%) induce a decreased fractional shortening and increased oxidative stress in ApoE KO mice. A transcriptomic analysis of the e-cigarettes (2.4%) treated ApoE KO mice model shows a change in genes associated with metabolism and inflam m ation. Free fatty acids (FFA) are able to induce the production of mitochondrial reactive oxygen species (ROS). Oxidative stress play a major role in the inflammatory, metabolic and contractile changes of the dysfunctional heart. While there are several sources of ROS, it is generally accepted that the dysfunctional mitochondria is the major source of ROS overproduction. Mitochondrial dysfunction and reduced NAD+ levels are implicated in various metabolic and cardiovascular pathologies. NAD+ is a central metabolic co-factor by virtue of its redox capacity, and as such, regulates a wealth of metabolic transformations and ROS production. Animal models for obesity and smoking have shown decreased levels of NAD+. Nicotinamide riboside (NR), a newly identified precursor of NAD+, increases NAD+ and protects mice against mitochondrial dysfunction and HFD-induced metabolic abnormalities. In this study our specific aims are: Aim 1 will demonstrate that e-cigarette-induced cardiac dysfunction requires lipolysis that will be blocked with lipolysis inhibitor, acipimox. Aim 2, I will demonstrate that NR reversesthe oxidative stress, mitochondrial abnormalities, and cardiac dysfunction induced by e-cigarettes. FFA and NAD+ levels might be useful therapeutic targets to counteract the detrimental cardiac effects of e-cigarettes. Our study is likely to provide information so that regulatory agencies and the public can understand some of the detrimental effects of e-cigarettes. My immediate goal would be using training from SC2 grant and my prior experiences on basic research to become independent and competent faculty at CDU. Eventually this will help me to secure RO1, SC1 and other foundation grants to establish my own research team focusing on the metabolic effects of e-cigarettes and cardiac dysfunction. 1

Espinoza-Derout，Jorge 项目概要：电子烟（电子烟）作为一种替代品在全球范围内变得非常受欢迎。传统香烟，无论是吸烟者还是从未吸烟的人。为研究e- 香烟，我使用了ApoE基因敲除（ApoE KO）小鼠，最常用的小鼠模型来研究传统香烟对心血管的影响将西方饮食（WD）的ApoE KO小鼠暴露于盐水，不含尼古丁的电子烟（电子烟（0%））和含2.4%尼古丁的电子烟（电子烟（2.4%））气雾剂 12周我们的初步数据显示，暴露于电子烟的小鼠（2.4%）的血清FFA与生理盐水和电子烟（0%）相比。此外，电子烟（2.4%）会导致 ApoE基因敲除小鼠缩短率降低和氧化应激增加。转录组学分析电子烟（2.4%）治疗的ApoE KO小鼠模型显示与代谢相关的基因发生变化，通货膨胀游离脂肪酸（FFA）能够诱导线粒体活性氧（ROS）的产生。氧化应激在功能失调的炎症、代谢和收缩变化中起主要作用心虽然ROS有几种来源，但通常认为功能障碍的线粒体是ROS的主要来源。 ROS过量产生的主要来源。线粒体功能障碍和NAD+水平降低与各种代谢和心血管疾病。NAD+是一种重要的代谢辅因子，能力，并因此调节大量的代谢转化和ROS产生。动物模型肥胖和吸烟都显示出NAD+水平降低。烟酰胺核苷（NR），一种新发现的 NAD+的前体，增加NAD+，并保护小鼠免受线粒体功能障碍和HFD诱导的代谢异常在这项研究中，我们的具体目标是：目标1将证明电子烟诱导的心脏功能障碍需要脂解作用，而脂解作用将被脂解抑制剂阿昔莫司阻断。目标2，我会表明NR逆转氧化应激、线粒体异常和心功能障碍由电子烟引起的。FFA和NAD+水平可能是有用的治疗目标，以抵消有害的电子烟对心脏的影响我们的研究可能会提供信息，以便监管机构和公众可以理解电子烟的一些有害影响。我的近期目标是利用SC2资助的培训和我以前在基础研究方面的经验，成为CDU独立而有能力的教师。最终，这将帮助我确保RO 1，SC 1和其他基金会赠款建立我自己的研究团队，专注于电子烟的代谢影响，心功能不全 1