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：
10440268
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10440268
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 Persons 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 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