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：
7884030
负责人：
MARSHA P COLE
金额：
$ 5.51万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7884030
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 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 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 public health relevance receptor respiratory response transcription factor

项目摘要

DESCRIPTION (provided by applicant): 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 7NO-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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：抽象的高血糖和高脂血症条件导致胰岛素介导的细胞信号传导和代谢异常的失调。 II型糖尿病中存在促氧化环境，导致心脏线粒体的活性氧和一氧化氮合酶活性增加。该建议的重点是一种中心假设：一类7NO依赖性的氧化和硝化产物，硝酸脂肪酸（NO2-FA）在高血糖条件下在心脏线粒体中产生，并且可以介导有益地改变线粒体功能的反应。 NO2-FA衍生物是内源性的，并通过主要依赖CGMP独立的机制介导抗炎症作用，包括电流后转化后蛋白质修饰和有效的过氧化物酶体增殖物激活受体（PPARG）配体活性。由于稳健的硫醇反应性，NO2-FA还通过与核因子E2相关因子2（NRF2）激活抗氧化剂反应元件（AS）相关基因表达的激活，在体外激活II期酶表达（例如血红素加氧酶1，HO-1）。当前的知识支持在II型糖尿病中，存在一种促进脂肪酸硝化的氧化环境。设计三个特定的目的是为了测试线粒体脂肪酸硝化发生的假设，并且这些物种可能有益地在II型糖尿病中进行有益地修饰线粒体和心血管功能：1）量化高血糖野生型和糖尿病的MITAILED MITAISTISTER MITA的线粒体产生NO2-FA是否会确定MIT n-NN-NNE-NEN-NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN NEN。在LEPOB糖尿病小鼠中，在OA-NO2给药后，在糖尿病级缺乏（OB/OB）鼠模型中的功能（OB/OB）模型和3）评估心脏收缩性，功能和氧气的变化。拟议的目标的完成将有助于洞察NO2-FA如何影响线粒体呼吸功能，心肌效率和心脏收缩率在鼠类糖尿病模型中。这项工作具有很大的临床相关性，因为它也将提供有关在高血糖引起的心肌损伤中形成的OA-NO2潜在疗效的洞察力。公共卫生相关性：这项工作具有很大的临床相关性，因为它也将提供有关在高血糖引起的心肌损伤中作为适应性细胞信号介质形成的OA-NO2潜在功效的见解。