Metabolic Stress-Induced Fatty Acid Nitration and Cardiovascular Function

代谢应激诱导的脂肪酸硝化与心血管功能

基本信息

批准号：
8413072
负责人：
MARSHA P COLE
金额：
$ 24.9万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8413072
关键词：
Action Potentials Age Agonist Anti-Inflammatory Agents Anti-inflammatory Antioxidants Appointment Biological Assay Biology Cardiac Cardiovascular Physiology Chemicals Complex Cyclic GMP DNA Data Diabetes Mellitus Diabetic mouse Diastolic blood pressure Diet Electrospray Ionization Enzymes Fatty Acids Gene Expression Heart Heart Mitochondria Heart Rate High Pressure Liquid Chromatography Homeostasis Hyperglycemia Hyperglycemic Mice In Vitro Individual Inflammation Mediators Inflammatory Injection of therapeutic agent Injury Insulin Ions Knowledge Lead Left Leptin Ligands Linoleic Acids Lipids Measurement Measures Mediating Mediator of activation protein Mentorship Metabolic Metabolic stress Mitochondria Mitochondrial Proteins Modeling Molecular Weight Monocyte Chemoattractant Protein-1 Mus Myocardial Myocardial dysfunction NF-kappa B Nitrates Nitric Oxide Nitric Oxide Synthase Non-Insulin-Dependent Diabetes Mellitus Nuclear Obesity Oleic Acids Oxidation-Reduction Oxidative Stress Oxygen Consumption PPAR gamma Peroxisome Proliferator-Activated Receptors Peroxonitrite Pharmacologic Actions Phase Play Polyunsaturated Fatty Acids Positioning Attribute Post-Translational Protein Processing Preparation Production Property Proteins Pump Reaction Reactive Oxygen Species Research Respiration Respiratory physiology Response Elements Risk Role Signal Transduction Spectrometry, Mass, Electrospray Ionization Sulfhydryl Compounds Superoxides Testing Time Tissues Treatment Efficacy Tumor Necrosis Factor-alpha Universities Up-Regulation Ventricular Work Workload abstracting adduct cardiovascular injury clinically relevant cytokine design diabetic falls feeding heart preservation heme oxygenase-1 in vivo insight nitration oxidation pressure protein complex receptor respiratory response transcription factor

项目摘要

Abstract Hyperglycemic and hyperlipidemic conditions lead to dysregulation of insulin mediated cell signaling and metabolic abnormalities. A pro-oxidative milieu exists in type II diabetes which results in increased cardiac mitochondrial production of reactive oxygen species and nitric oxide synthase activity. This proposal focuses on the central hypothesis that one class of ¿NO-dependent oxidation and nitration products, nitrated fatty acids (NO2-FA), are generated in heart mitochondria under hyperglycemic conditions and can mediate reactions that beneficially modify mitochondrial function. NO2-FA derivatives are present endogenously and mediate anti- inflammatory effects through predominately cGMP-independent mechanisms that include electrophilic post- translational protein modification and potent peroxisome proliferator-activated receptor (PPARg) ligand activity. As a result of robust thiol reactivity, NO2-FA also activate phase II enzyme expression in vitro (e.g., heme oxygenase 1, HO-1), through nuclear factor E2-related factor 2 (Nrf2) activation of antioxidant response element (ARE) dependent gene expression. Current knowledge supports that in type II diabetes, a pro- oxidative milieu exists that promotes fatty acid nitration. Three specific aims are designed to test the hypothesis that mitochondrial fatty acid nitration occurs and that these species may beneficially modify mitochondrial and cardiovascular function in type II diabetes: 1) quantify the mitochondrial production of NO2- FA in hyperglycemic wildtype and diabetic Lepob mice, 2) determine whether administered OA-NO2 modulates mitochondrial function in a diabetic-leptin deficient (ob/ob) murine model, and 3) assess changes in cardiac contractility, function, and oxygen consumption following OA-NO2 administration in Lepob diabetic mice. Completion of the proposed aims will lend insight into how NO2-FA can impact mitochondrial respiratory function, myocardial efficiency, and cardiac contractility in a murine model of diabetes. This work is of substantial clinical relevance as it will also provide insight as to the potential efficacy of OA-NO2 formed as an adaptive cell signaling mediator in hyperglycemic-induced myocardial injury.

抽象的高血糖和高脂血症状况导致胰岛素介导的细胞信号传导和代谢异常。 II型糖尿病中存在促氧化环境，导致心脏增加活性氧和一氧化氮合酶活性的线粒体产生。该提案重点是关于一类无依赖性氧化和硝化产物的中心假设，硝化脂肪酸（NO2-FA）在高血糖条件下在心脏线粒体中产生有益修改线粒体功能。 NO2-FA衍生物是内源性的，并介导通过主要依赖CGMP的机制，包括电亲电的机制，炎症作用翻译蛋白质的修饰和潜在的过氧化物体增殖物激活受体（PPARG）配体活性。由于稳健的硫醇反应性，NO2-FA还在体外激活II期酶表达（例如，血红素通过核因子E2相关因子2（NRF2）激活抗氧化剂反应，氧合酶1，HO-1）元素（为）依赖基因表达。当前的知识支持在II型糖尿病中存在促进脂肪酸硝化的氧化环境。三个特定目标旨在测试线粒体脂肪酸硝化发生的假设，这些物种可能会有益地改变 II型糖尿病中的线粒体和心血管功能：1）量化NO2-的线粒体产生高血糖野生型和糖尿病性鳞茎小鼠中的FA，2）确定是否给予OA-NO2调节糖尿病 - 肠道缺乏（OB/OB）鼠模型的线粒体功能和3）心脏评估变化 LEPOB糖尿病小鼠OA-NO2给药后的收缩力，功能和氧气消耗。拟议的目标的完成将洞悉NO2-FA如何影响线粒体呼吸道糖尿病的鼠模型中的功能，心肌效率和心脏收缩性。这项工作是实质性的临床相关性，因为它也将提供有关形成的OA-NO2潜在效率的见解高血糖引起的心肌损伤中的自适应细胞信号介体。