Epoxyeicosatrienoic acids, diabetes, and cardiovascular disease

 描述(申请人提供)：2型糖尿病已经在世界范围内达到流行的程度，并带有很高的心血管发病率和死亡率负担。这项应用旨在确定新的可修改因素，即血浆环氧二十碳三烯酸(EET)种类，与糖尿病和糖尿病相关心血管疾病的风险相关。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。内毒素是花生四烯酸的衍生物，在血管内皮细胞、胰腺、心脏和脑中具有重要的功能。在糖尿病或胰岛素抵抗的动物模型中，由于CYP2J2的过度表达或抑制可溶性环氧化物水解酶而导致的EET水平升高，降低了血糖和胰岛素水平，改善了糖耐量，改善了胰岛素的分泌，减少了胰岛细胞的凋亡，提示其在糖尿病的病理生理机制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、中风和心肌病的发生联系起来。这些发现与人类遗传相关性研究的证据一起，使我们假设血浆EET与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调查这些假设，一项是关于来自13个不同部落的美国印第安人心血管疾病风险因素的社区前瞻性研究，另一项是心血管健康研究，一项关于老年人心血管疾病风险因素的前瞻性研究。使用最先进的方法，我们将从总共4000名研究参与者的现有样本中测量4种EET，并将这些新数据与现有的关于风险因素的信息和后续数据结合起来，以检查以下具体目标：(目标1)前瞻性地检查EET与糖尿病发病(Aim 1a)、非糖尿病参与者中空腹血糖、空腹胰岛素、HOMA-IR(胰岛素抵抗的稳态模型评估)和血红蛋白A1c的变化(Aim1b)以及与糖尿病参与者中发生的心血管疾病(包括心肌梗死、缺血性中风和心力衰竭)(Aim 1c)的关系。在目标2中，我们将使用体外系统来研究在2型糖尿病期间，CYP2J2下调，导致EETs降低，是否与人类心肌细胞代谢应激有关，我们将确定CYP2J2调节的途径，介导对糖尿病的反应。总而言之，这些互补的目标将确定EET与糖尿病和糖尿病相关心血管疾病风险之间的关联，同时还将确定糖尿病扰乱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械洞察力联系起来，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.