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：
7533606
负责人：
Demetra Christou
金额：
$ 6.28万
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 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7533606
关键词：
3-nitrotyrosine 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 Condition 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 Outcome 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 Resolution Risk Factors Role Site Source Superoxide Dismutase System Techniques Testing Thinking 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 prevent protein expression reactive hyperemia response 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）：代谢综合征是由代谢和血管起源的相互关联风险因素的聚类定义的，是影响约4700万美国居民的主要公共卫生问题。在约44％以上的50岁以上男性和女性中，中年和老年人的代谢综合征的患病率特别高。衰老和代谢综合征与心血管疾病和死亡的风险增加有关。动脉粥样硬化是导致心血管发病率和死亡率的主要因素。血管内皮功能障碍是动脉粥样硬化发病机理的关键早期事件，在代谢综合征和老年人中很常见。但是，对此损害的机制知之甚少。拟议的研究将确定对中年和老年人患有代谢综合征的老年人和老年人的临床相关标志，矿物皮质激素受体的阻断是否改善了血管内皮依赖性扩张。我们还将研究氧化应激和炎症在介导这些有益作用中的作用。我们的工作假设是，矿物皮质激素受体阻滞将导致内皮依赖性扩张的改善。这种改善将与氧化应激和炎症的生物标志物的更大减少有关。这些生物标志物的基线水平升高的人将在封锁后会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，跨界研究。测量将在矿物皮质受体阻滞后（eplerenone）和安慰剂后一次（即控制状态）进行两次测量。内皮依赖性扩张（臂动脉流介导的扩张）和内皮非依赖性扩张（对舌下硝酸甘油的响应臂动脉膨胀）将使用高分辨率双重超声进行非侵袭性确定。洞悉介导的矿物皮质激素受体阻断后血管内皮功能损伤和改善的分子机制将使用一种新型的转化研究技术来获得，该技术通过定量免疫荧光通过定量免疫荧光来收集人内皮细胞并确定促蛋白质内皮细胞的蛋白质表达。还将在血液中确定氧化应激和炎症的全身生物标志物。预期的结果应显着扩展我们对衰老血管内皮功能障碍和代谢综合征的血管内皮功能障碍下的综合（全身）生理机制的当前理解。这些发现可能对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的发展具有重要意义。公共卫生相关性：由多个心血管危险因素共存定义的代谢综合征是一个主要的公共卫生问题。代谢综合征的发生在中年和老年人中尤为高。拟议的研究将研究中年和老年人的代谢综合征，矿物皮质激素受体是否有助于血管内皮功能障碍，这是动脉粥样硬化发展的关键早期事件。