Epoxyeicosatrienoic acids, diabetes, and cardiovascular disease

环氧二十碳三烯酸、糖尿病和心血管疾病

基本信息

批准号：
9004661
负责人：
Rozenn Lemaitre
金额：
$ 70.18万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-15 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9004661
关键词：
Acids American Indians Anabolism Animal Model Apoptosis Arachidonic Acids Atherosclerosis Brain CYP2J2 gene Calcium Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cardiovascular system Communities Coronary heart disease Coupling Cytochrome P450 Data Development Diabetes Mellitus Disease Down-Regulation Elderly Enzymes Epidemic Epoxide hydrolase Exposure to Family Study Fasting Functional disorder Future Genetic Polymorphism Genetic Transcription Glucose Heart Heart failure Hemoglobin Human In Vitro Insulin Insulin Resistance Ischemic Stroke Islet Cell Isomerism Link Lipids Mass Spectrum Analysis Measures Mediating Metabolic Metabolic Marker Metabolic stress Metabolism Methodology Modeling Morbidity - disease rate Muscle Cells Myocardial Infarction Myocardial Ischemia Myocardial Reperfusion Non-Insulin-Dependent Diabetes Mellitus Oxidative Stress PPAR gamma Pancreas Participant Pathway interactions Patients Plasma Population Prevention Prospective Studies Public Health Reactive Oxygen Species Regulation Risk Risk Factors Role Sampling Serum Stimulus Stroke Structure of beta Cell of islet System Testing Time Tribes Vascular Endothelium Ventricular base cardiovascular health cohort diabetes risk diabetic diabetic patient early onset fasting glucose fighting follow-up genetic association glucose tolerance high risk improved in vivo innovation insight insulin secretion mortality novel overexpression population based prevent public health relevance research study response transcriptomics

项目摘要

DESCRIPTION (provided by applicant): Type 2 diabetes has reached epidemic proportions world-wide and carries a high burden of cardiovascular morbidity and mortality. This application seeks to identify novel modifiable factors, namely plasma epoxyeicosatrienoic acid (EET) species, associated with risks of incident diabetes and diabetes-associated incident cardiovascular disease. In addition, we will study the influence of serum from diabetic patients on EET metabolism and regulation in human cardio-myocytes. EETs are arachidonic acid derivatives with important functions in vascular endothelium, pancreas, heart and brain. In animal models of diabetes or insulin resistance, increased EET levels from overexpression of CYP2J2 or inhibition of soluble epoxide hydrolase, reduce glucose and insulin levels, improve glucose tolerance, improve insulin secretion and reduce islet cell apoptosis, suggesting a potentially important role in the pathophysiology of diabetes. In addition, manipulation of EET levels in animal models has linked these metabolites to the development of atherosclerosis, heart failure, myocardial ischemia and reperfusion, stroke and cardiomyopathy. These findings together with evidence from genetic association studies in humans led us to hypothesize that plasma EETs are associated with lower risks of incident diabetes and diabetes-related cardiovascular disease. We will investigate these hypotheses in two prospective studies, the Strong Heart Family Study, a community-based, prospective study of risk factors for cardiovascular disease among American Indians from 13 different tribes, and the Cardiovascular Health Study, a prospective study of risk factors for cardiovascular disease among older adults. Using state-of-the-art methodology, we will measure 4 EET species in plasma from existing samples from 4000 total study participants, and combine these new data with existing information on risk factors and follow-up data to examine the following specific aims: (Aim 1) To prospectively examine the associations of EETs with incident diabetes (Aim 1a), changes in fasting glucose, fasting insulin, HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) and hemoglobin A1C among participants without diabetes (Aim1b), and with incident cardiovascular disease (including myocardial infarction, ischemic stroke, and heart failure) among participants with diabetes (Aim 1c). In Aim 2, we will use an in vitro system to investigate whether CYP2J2 down regulation, resulting in lower EETs, contributes to human cardio-myocyte metabolic stress during type 2 diabetes, and we will identify CYP2J2- regulated pathways mediating the response to diabetes. Collectively, these complementary aims will determine the associations between EETs and risks of incident diabetes and diabetes-associated CVD, while also identifying mechanisms through which diabetes perturbs EET pathways and promotes cardio-myocyte dysfunction. By linking clinically meaningful endpoints with mechanistic insights, this project creates a roadmap for innovative approaches to prevent and treat diabetes and its complications.

描述（由申请人提供）：2 型糖尿病已在世界范围内达到流行程度，并带来较高的心血管发病率和死亡率负担。本申请旨在确定与 2 型糖尿病风险相关的新的可改变因素，即血浆环氧二十碳三烯酸 (EET) 种类。此外，我们还将研究糖尿病患者血清对花生四烯酸 EET 代谢和调节的影响。在血管内皮、胰腺、心脏和大脑中具有重要功能的衍生物在糖尿病或胰岛素抵抗的动物模型中，由于CYP2J2的过度表达或可溶性环氧化物水解酶的抑制而增加EET水平，降低葡萄糖和胰岛素水平，改善葡萄糖耐量，改善胰岛素分泌。并减少胰岛细胞凋亡，这表明在糖尿病的病理生理学中具有潜在的重要作用。此外，在动物模型中控制 EET 水平已将这些代谢物与动脉粥样硬化、心脏的发展联系起来。这些发现与人类遗传关联研究的证据一起使我们重新认识到血浆 EET 与降低糖尿病和糖尿病相关心血管疾病的风险有关。两项前瞻性研究，强心家族研究（Strong Heart Family Study）是一项以社区为基础的前瞻性研究，针对来自 13 个不同部落的美洲印第安人的心血管疾病危险因素进行研究；心血管健康研究（Cardioangio Health Study）是一项针对老年人心血管疾病危险因素的前瞻性研究。使用采用最先进的方法，我们将从 4000 名研究参与者的现有样本中测量血浆中的 4 种 EET 物种，并将这些新数据与现有信息相结合，结合风险因素和后续数据来检查以下具体目标：（目标 1) 前瞻性研究 EET 与糖尿病发病率（目标 1a）、空腹血糖变化、空腹胰岛素、HOMA-IR（胰岛素抵抗稳态模型评估）和血红蛋白的关系无糖尿病参与者（目标 1b）和患有心血管疾病（包括心肌梗死、缺血性中风和心力衰竭）的糖尿病参与者（目标 1c）的 A1C 在目标 2 中，我们将使用体外系统来研究 CYP2J2 是否存在。下调导致 EET 降低，导致 2 型糖尿病期间人类心肌细胞代谢应激，我们将确定 CYP2J2 调节的途径来介导糖尿病反应。这些事件的互补目标将确定 EET 与糖尿病和糖尿病相关 CVD 风险之间的关联，同时还确定糖尿病扰乱 EET 途径并促进心肌细胞功能障碍的机制。通过将具有临床意义的终点与机制见解联系起来，该项目创建了一个预防和治疗糖尿病及其并发症的创新方法路线图。