Epoxyeicosatrienoic acids, diabetes, and cardiovascular disease

环氧二十碳三烯酸、糖尿病和心血管疾病

• 批准号: 9195147
• 负责人: Rozenn Lemaitre
• 金额: $ 70.28万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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/9195147
• 关键词: Acids; American Indians; Anabolism; Animal Model; Apoptosis; Arachidonic Acids; Atherosclerosis; Brain; CYP2J2 gene; Calcium; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Clinical; 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; Glycosylated hemoglobin A; Heart; Heart failure; 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 Study; 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; cardiovascular risk factor; cohort; diabetes risk; diabetic; diabetic patient; early onset; experimental study; fasting glucose; fighting; follow-up; genetic association; glucose tolerance; high risk; high risk population; improved; in vivo; innovation; insight; insulin secretion; mortality; novel; overexpression; population based; prevent; prospective; public health relevance; response; transcriptomics

 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（通过应用程序提供）：2型糖尿病已在全球范围内达到流行比例，并具有高度的心血管发病率和死亡率。该应用程序旨在确定可改变的新因素，即血浆环氧酸性酸（EET）物种，与出现糖尿病和糖尿病相关的入射心血管疾病的风险相关。此外，我们将研究糖尿病患者的血清对人类心肌细胞中EET代谢和调节的影响。 EET是具有重要功能的蛛网膜酸衍生物，在血管植物，胰腺，心脏和大脑中。在糖尿病和胰岛素抵抗的动物模型中，CYP2J2过表达或抑制固体环氧水解酶，降低葡萄糖和胰岛素水平，提高葡萄糖耐受性，改善胰岛素的分泌并减少胰岛细胞凋亡，提高胰岛细胞凋亡，表明在糖尿病学病理生理学中具有潜在的重要作用。此外，动物模型中EET水平的操纵将这些代谢产物与动脉粥样硬化，心力衰竭，心肌缺血和再灌注，中风和心肌病的发展联系起来。这些发现以及人类遗传关联研究的证据，使我们假设血浆EET与较低的糖尿病和糖尿病相关心血管疾病的风险较低有关。我们将在两项前瞻性研究中研究这些假设，即强有力的心脏家庭研究，这是一项基于社区的，对来自13个不同部落的美洲印第安人心血管疾病危险因素的前瞻性研究，以及心血管健康研究，这是对老年人心血管疾病风险因素的前瞻性研究。 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糖尿病参与者（AIM 1C）中，没有糖尿病（AIM1B）的参与者（AIM1B）以及入射心血管疾病（包括心肌梗塞，缺血性中风和心力衰竭）的血红蛋白A1C（AIM 1C）。在AIM 2中，我们将使用一个体外系统来研究CYP2J2降低调节（导致较低的EET）是否有助于2型糖尿病期间人类心脏肌细胞代谢应激，我们将识别CYP2J2调节的途径，介导对糖尿病的反应。总的来说，这些补充目标将确定EET与与糖尿病相关的CVD的ETES与风险之间的关联，同时还确定了糖尿病伴有EET途径的机制，并促进了心成年细胞功能障碍。通过将临床意义的终点与机械见解联系起来，该项目为预防和治疗糖尿病及其并发症的创新方法创建了路线图。