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，豪尔赫项目摘要：电子烟（电子烟）在全球范围内变得非常流行，作为替代品在吸烟者和从未吸烟的人中，传统的香烟。研究E-的心脏效应香烟，我使用了Apoe敲除（Apoe KO）小鼠，这是最常用的鼠模型来研究常规香烟的心血管效应。 apoe ko miceon A Western Diet（WD）暴露于盐水中，没有尼古丁的电子烟（电子烟（0％））和2.4％尼古丁（电子烟（2.4％））气溶胶的电子烟和电子烟 12周。我们的初步数据表明，暴露于电子烟的小鼠（2.4％）的水平增加血清FFA与盐水和电子烟（0％）相比。此外，电子烟（2.4％）诱导A APOE KO小鼠中的分数缩短和氧化应激的增加。对电子烟（2.4％）处理过的APOE KO小鼠模型显示出与代谢和代谢相关的基因变化 inflam m ation。游离脂肪酸（FFA）能够诱导线粒体活性氧（ROS）的产生。氧化应激在功能障碍的炎症，代谢和收缩变化中起主要作用心。虽然有几种ROS来源，但通常认为线粒体功能失调是 ROS过量生产的主要来源。线粒体功能障碍和降低的NAD+水平与各种代谢和心血管病理。 NAD+由于其氧化还原而是中央代谢辅助因素能力，因此调节了大量的代谢转型和ROS生产。动物模型肥胖和吸烟显示NAD+的水平降低。烟酰胺核苷（NR），新近识别 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，我们的具体目的是：AIM 1将证明电子烟引起的心脏功能障碍需要脂解，该脂解会被脂解抑制剂Acipimox封闭。目标2，我会证明NR反转氧化应激，线粒体异常和心脏功能障碍由电子烟诱导。 FFA和NAD+水平可能是有用的治疗靶标，可以抵消有害的电子烟的心脏影响。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某些有害影响。我的直接目标是使用SC2 Grant的培训以及我先前在基础研究方面的经验成为CDU的独立和称职的教师。最终，这将帮助我确保RO1，SC1和其他基金会授予建立我自己的研究团队，专注于电子烟的代谢影响和心脏功能障碍。 1