Diabetes, Estrogen and Endothelial Dysfunction

糖尿病、雌激素和内皮功能障碍

基本信息

批准号：
9165039
负责人：
ROSHANAK RAHIMIAN
金额：
$ 30.24万
依托单位：
UNIVERSITY OF THE PACIFIC-STOCKTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-25 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9165039
关键词：
Adult Affect Age Animal Model Atherosclerosis Beta Cell Biological Availability Blood Vessels Cardiovascular Diseases Cardiovascular system Characteristics Clinical Contracts Data Development Diabetes Mellitus Disease Endothelial Cells Endothelin-1 Endothelium Epidemiology Epoprostenol Estrogens Event Failure Female Functional disorder Genes Glucose Goals Gonadal Steroid Hormones Homeostasis Human Hyperglycemia Incidence Insulin-Dependent Diabetes Mellitus Knowledge Mediating Mesenteric Arteries Modeling Molecular Morbidity - disease rate NADPH Oxidase Nature Nitric Oxide Non-Insulin-Dependent Diabetes Mellitus Obesity Pathway interactions Patients Persons Play Population Postmenopause Premenopause Production Prostaglandins I Protein Kinase C Rattus Regulation Relative Risks Relaxation Reporting Research Risk Role Sex Characteristics Signal Transduction Superoxides Testing Thromboxane A2 Time Vascular Diseases Woman base cardiovascular disorder risk diabetic diabetic patient diabetic rat endothelial dysfunction experience innovation insight male men mortality non-diabetic novel protein kinase C beta renal artery sex spatiotemporal stem

项目摘要

Diabetes mellitus affects more than 300 million persons worldwide and the number of diabetic patients is estimated to rise by more than 50% within 20 years. Cardiovascular diseases (CVD) are the leading cause of mortality and morbidity in diabetic patients, and a crucial early step, endothelial dysfunction, contributes to the development of atherosclerosis and subsequent cardiovascular complications. The risk for CVD is lower in premenopausal women compared to age-matched men. This difference disappears in the postmenopausal years and is presumably related to the reduced levels of female sex hormones, in general, and estrogen, in particular. However, premenopausal women with diabetes not only lose this sex-based cardiovascular protection, they actually experience a higher relative risk of CVD compared to diabetic men, which suggests that diabetes abrogates some of the beneficial effects of estrogen. Given this epidemiological evidence, the question arises as to what mechanisms underlie the loss of sex- mediated vasoprotection in diabetic women. This proposal will explore the basis for the loss of sex-based cardiovascular protection. We aim specifically to investigate estrogen-mediated signaling events associated with vascular tone and endothelial function in diabetic and non-diabetic rats, as well as in human endothelial cells exposed to normal or high concentrations of glucose. We recently reported sex differences with regard to endothelial dysfunction in type 1 diabetes (T1D). However, the pathophysiology of Type 2 diabetes (T2D) may differ from that seen in T1D, and it is known that the incidence of T2D is rapidly increasing worldwide. Therefore, we propose to examine vascular function in mesenteric and renal arteries using an established obesity-induced T2D animal model, the Zucker diabetic fatty (ZDF) rat. We will also characterize, for the first time, the vascular function in a novel model of T2D (UC Davis-T2D Mellitus, UCD-T2DM). UCD-T2DM rats appear to more closely resemble the human condition, sharing all of the key features of the disease. We intend to test the central hypothesis that diabetes abolishes the vasoprotective actions of estrogen due to an alteration of estrogen-mediated signaling events associated with the release/bioavailability of endothelium-derived relaxing and/or constricting factors. We further hypothesize that the molecular basis for the diabetes-induced loss of vasoprotection involves an alteration in estrogen-modulated regulation of 1) the activity and expression of specific genes that are associated with arterial function, and/or 2) Ca2+ transport in the endothelial cells. The novelty of this proposal is that we will 1) compare vascular reactivity in a novel model of T2D to that observed in an established model of T2D and 2) test the hypothesis that changes in the spatiotemporal characteristics of Ca2+ signaling may contribute to the loss of estrogen-dependent vasoprotection in diabetic females. The significance of this proposal lies in the uncovering mechanisms that may contribute to the beneficial and detrimental effects of estrogen on vascular cell signaling in healthy and pathological conditions such as T2D.

糖尿病影响全球超过 3 亿人，糖尿病患者数量预计20年内将增长50%以上。心血管疾病（CVD）是主要原因糖尿病患者的死亡率和发病率，以及关键的早期步骤，内皮功能障碍，有助于动脉粥样硬化和随后的心血管并发症的发展。 CVD 的风险是与同龄男性相比，绝经前女性的这一比例较低。这种差异在绝经后几年，可能与女性性激素水平降低有关，一般而言，尤其是雌激素。然而，患有糖尿病的绝经前女性不仅会损失这种基于性别的心血管保护措施，实际上与其他人相比，他们患心血管疾病的相对风险更高糖尿病男性，这表明糖尿病消除了雌激素的一些有益作用。鉴于此流行病学证据表明，性丧失背后的机制是什么？介导糖尿病女性的血管保护作用。该提案将探讨基于性别的丧失的基础心血管保护。我们的具体目标是研究雌激素介导的信号事件相关与糖尿病和非糖尿病大鼠以及人类内皮细胞的血管张力和内皮功能有关细胞暴露于正常或高浓度的葡萄糖。我们最近报告了以下方面的性别差异 1 型糖尿病 (T1D) 中的内皮功能障碍。然而，2 型糖尿病 (T2D) 的病理生理学可能与 T1D 不同，众所周知，T2D 的发病率在全球范围内迅速增加。因此，我们建议使用已建立的方法来检查肠系膜和肾动脉的血管功能。肥胖诱导的 T2D 动物模型，Zucker 糖尿病肥胖 (ZDF) 大鼠。我们还将首次描述，新型 T2D 模型（UC Davis-T2D Mellitus，UCD-T2DM）中的血管功能。 UCD-T2DM 大鼠似乎更接近人类的状况，具有该疾病的所有关键特征。我们打算测试核心假设是，糖尿病由于雌激素的改变而消除了雌激素的血管保护作用雌激素介导的信号事件与内皮源性松弛的释放/生物利用度相关和/或限制因素。我们进一步假设糖尿病引起的丧失的分子基础血管保护涉及雌激素调节的改变 1) 活性和表达与动脉功能相关的特定基因，和/或 2) 内皮细胞中的 Ca2+ 转运。这该提案的新颖之处在于我们将 1) 将新型 T2D 模型中的血管反应性与观察到的进行比较在已建立的 T2D 模型中，2）检验以下假设：时空特征发生变化 Ca2+ 信号传导可能导致女性糖尿病患者雌激素依赖性血管保护作用的丧失。这该提案的意义在于揭示可能有助于有益和有益的机制雌激素对 T2D 等健康和病理条件下血管细胞信号传导的有害影响。