Epoxyeicosatrienoic acids, diabetes, and cardiovascular disease

 描述（由申请人提供）：2型糖尿病已在世界范围内达到流行比例，并带来心血管发病率和死亡率的高负担。本申请寻求鉴定新的可改变的因子，即血浆环氧二十碳三烯酸（EET）种类，其与糖尿病和糖尿病相关的心血管疾病的发病风险相关。此外，我们还将研究糖尿病患者血清对人心肌细胞EET代谢和调节的影响。雌二醇是花生四烯酸衍生物，在血管内皮、胰腺、心脏和脑中具有重要功能。在糖尿病或胰岛素抵抗的动物模型中，由于CYP2J2的过表达或可溶性环氧化物水解酶的抑制而增加的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，在动物模型中对EET水平的操纵已经将这些代谢物与动脉粥样硬化、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。这些发现以及来自人类遗传关联研究的证据使我们假设血浆雌二醇与糖尿病和糖尿病相关心血管疾病的风险降低相关。我们将在两项前瞻性研究中调查这些假设，强心家族研究，一项基于社区的前瞻性研究，来自13个不同部落的美洲印第安人心血管疾病的危险因素，以及心血管健康研究，一项前瞻性研究，老年人心血管疾病的危险因素。使用最先进的方法，我们将测量来自4000名研究参与者的现有样本中血浆中的4种EET物质，并将这些新数据与风险因素和随访数据的现有信息结合联合收割机，以检查以下特定目标：（目的1）前瞻性研究Ekl2与糖尿病发病率（目的1a）、空腹血糖、空腹胰岛素、HOMA-IR（胰岛素抵抗稳态模型评估）和血红蛋白A1C在无糖尿病的参与者中（Aim1b），以及在糖尿病参与者中（Aim1c）发生心血管疾病（包括心肌梗死、缺血性卒中和心力衰竭）。在目标2中，我们将使用体外系统来研究CYP2J2下调是否导致2型糖尿病期间较低的Ehrs，有助于人类心肌细胞代谢应激，并且我们将确定CYP2J2调节的途径介导对糖尿病的反应。总的来说，这些互补的目标将确定EET与糖尿病和糖尿病相关CVD风险之间的关联，同时还确定糖尿病干扰EET途径并促进心肌细胞功能障碍的机制。通过将临床上有意义的终点与机制性见解联系起来，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。

 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.