Endothelial Dysfunction in Older Adult Humans with the Metabolic Syndrome

患有代谢综合征的老年人的内皮功能障碍

基本信息

批准号：
7685291
负责人：
Demetra Christou
金额：
$ 3.9万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2010-08-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7685291
关键词：
1 year old 3-nitrotyrosine Adult Affect Age Age-Years Aging Antiatherogenic Antioxidants Atherosclerosis Biological Availability Biological Markers Blood Blood Vessels Cardiovascular system Cells Central obesity Cessation of life Coagulation Process Cross-Over Studies Data Development Double-Blind Method Dyslipidemias Elderly Endothelial Cells Endothelium Enzymes Equilibrium Event Free Radicals Functional disorder Generations Homeostasis Human Hyperglycemia Hypertension Immunofluorescence Immunologic Impairment Individual Inflammation Interleukin-6 Lead Measurement Mediating Metabolic Metabolic syndrome Mineralocorticoid Receptor Molecular Morbidity - disease rate NADPH Oxidase Nitric Oxide Nitric Oxide Synthase Nitroglycerin Oxidants Oxidative Stress Pathogenesis Patients Physiological Physiology Placebos Platelet aggregation Play Post-Translational Protein Processing Prevalence Production Proteins Public Health Randomized Reactive Oxygen Species Relaxation Research Research Technics Resolution Risk Factors Role Site Source Superoxide Dismutase System Techniques Testing Thrombus Time Translational Research Ultrasonography Urine Vascular Endothelial Cell Vascular Endothelium Vasodilation Woman Work brachial artery cardiovascular disorder risk cardiovascular risk factor catalase clinically relevant eplerenone experience functional improvement improved insight men middle age monolayer mortality novel premature prevent primary outcome protein expression public health relevance reactive hyperemia response secondary outcome vascular endothelial dysfunction vascular inflammation vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): The metabolic syndrome, defined by a clustering of interrelated risk factors of metabolic and vascular origin, is a major public-health issue affecting ~47 million US residents. The prevalence of the metabolic syndrome is especially high in middle-aged and older adults occurring in ~44% of men and women over 50 years of age. Aging and the metabolic syndrome are associated with increased risk for cardiovascular disease and death. Atherosclerosis is the major contributor to cardiovascular morbidity and mortality. Vascular endothelial dysfunction, a critical early event in the pathogenesis of atherosclerosis, is common in patients with the metabolic syndrome, as well as in older adults. However, the mechanisms responsible for this impairment are poorly understood. The proposed research will determine if blockade of the mineralocorticoid receptors improves vascular endothelium-dependent dilation, a clinically relevant marker of endothelial function, in middle-aged and older adults with the metabolic syndrome. We will also investigate the role of oxidative stress and inflammation in mediating these beneficial effects. Our working hypothesis is that mineralocorticoid receptor blockade will lead to improved endothelium-dependent dilation. This improvement will be associated with greater reductions in biomarkers of oxidative stress and inflammation. Individuals with elevated baseline levels of these biomarkers will experience the greatest improvement in vascular endothelial function after the blockade. To test our working hypothesis we will conduct a balanced randomized, double-blind, cross-over study. Measurements will be performed twice, once after mineralocorticoid receptor blockade (Eplerenone) and once after placebo (i.e., control condition). Endothelium-dependent dilation (brachial artery flow mediated dilation) and endothelium-independent dilation (brachial artery dilation in response to sublingual nitroglycerin) will be determined non-invasively using high resolution duplex ultrasonography. Insight to the molecular mechanisms mediating the impairment in vascular endothelial function and improvement following mineralocorticoid receptor blockade will be obtained using a novel translational research technique of collecting human endothelial cells and determining protein expression of pro- and anti-atherogenic factors via quantitative immunofluorescence. Systemic biomarkers of oxidative stress and inflammation will also be determined in blood. The expected results should significantly extend our current understanding of the integrative (whole-body to molecular) physiological mechanisms underlying vascular endothelial dysfunction in aging and the metabolic syndrome. These findings may have important implications in the development of strategies for preventing and treating atherosclerosis associated with aging and the metabolic syndrome. PUBLIC HEALTH RELEVANCE: The metabolic syndrome, defined by the coexistence of multiple cardiovascular risk factors, is a major public- health issue. The occurrence of the metabolic syndrome is especially high in middle-aged and older adults. The proposed study will investigate in middle-aged and older adults with the metabolic syndrome, whether mineralocorticoid receptors contribute to vascular endothelial dysfunction, a key early event in the development of atherosclerosis.

描述（由申请人提供）：代谢综合征由代谢和血管起源的一系列相互关联的危险因素定义，是影响约 4700 万美国居民的主要公共卫生问题。代谢综合征在中老年人中的患病率尤其高，50 岁以上男性和女性的发病率约为 44%。衰老和代谢综合征与心血管疾病和死亡风险增加有关。动脉粥样硬化是心血管疾病发病率和死亡率的主要原因。血管内皮功能障碍是动脉粥样硬化发病机制中的一个关键早期事件，在代谢综合征患者以及老年人中很常见。然而，人们对造成这种损害的机制知之甚少。拟议的研究将确定阻断盐皮质激素受体是否可以改善患有代谢综合征的中老年人的血管内皮依赖性扩张（内皮功能的临床相关标志物）。我们还将研究氧化应激和炎症在调节这些有益作用中的作用。我们的工作假设是盐皮质激素受体阻断将改善内皮依赖性扩张。这种改善将与氧化应激和炎症生物标志物的更大减少相关。这些生物标志物基线水平升高的个体在阻断后将经历血管内皮功能的最大改善。为了检验我们的工作假设，我们将进行一项平衡的随机、双盲、交叉研究。测量将进行两次，一次在盐皮质激素受体阻断剂（依普利酮）之后，一次在安慰剂（即对照条件）之后。内皮依赖性扩张（肱动脉血流介导的扩张）和内皮非依赖性扩张（舌下含服硝酸甘油引起的肱动脉扩张）将使用高分辨率双重超声检查进行非侵入性测定。通过收集人内皮细胞并通过定量免疫荧光测定促动脉粥样硬化因子和抗动脉粥样硬化因子的蛋白质表达的新型转化研究技术，将获得对盐皮质激素受体阻断后介导血管内皮功能损伤和改善的分子机制的深入了解。氧化应激和炎症的全身生物标志物也将在血液中测定。预期结果将显着扩展我们目前对衰老和代谢综合征中血管内皮功能障碍的综合（全身到分子）生理机制的理解。这些发现可能对制定预防和治疗与衰老和代谢综合征相关的动脉粥样硬化的策略具有重要意义。公共卫生相关性：代谢综合征是由多种心血管危险因素并存定义的，是一个重大的公共卫生问题。代谢综合征的发生率在中老年人中尤其高。拟议的研究将调查患有代谢综合征的中老年人，盐皮质激素受体是否会导致血管内皮功能障碍，这是动脉粥样硬化发展的关键早期事件。