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: 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
• 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

 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.