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

• 批准号: 8137543
• 负责人: Demetra Christou
• 金额: $ 2.38万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8137543
• 关键词: Endothelial; Dysfunction; Older; Adult; Humans

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关危险因素聚集而成的，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群中患病率特别高，50岁以上的男性和女性患病率约为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的关键早期事件，在代谢综合征患者和老年人中很常见。然而，造成这种损伤的机制尚不清楚。拟议的研究将确定阻断矿皮质激素受体是否能改善中老年代谢综合征患者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介导这些有益作用中的作用。我们的工作假设是，矿化皮质激素受体阻断将导致改善内皮依赖性扩张。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。这些生物标志物基线水平升高的个体在阻断后血管内皮功能的改善最大。为了验证我们的假设，我们将进行一项平衡的、随机的、双盲的交叉研究。测量将进行两次，一次是在矿皮质激素受体阻断（Eplerenone）后，一次是在安慰剂（即对照条件）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（舌下硝酸甘油引起的肱动脉扩张）将采用高分辨率双相超声无创检测。利用一种新的转化研究技术，收集人内皮细胞，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表达，将获得介导血管内皮功能损伤和矿皮质激素受体阻断后改善的分子机制。氧化应激和炎症的系统生物标志物也将在血液中测定。预期的结果将显著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：代谢综合征是由多种心血管危险因素共存所定义的，是一个重大的公共卫生问题。代谢综合征在中老年人中发病率特别高。这项拟议的研究将调查中老年代谢综合征患者，矿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一个关键早期事件。

项目成果

Role of mineralocorticoid receptors in arterial stiffness in human aging.

• DOI: 10.1016/j.exger.2013.05.058
• 发表时间: 2013-08
• 期刊: EXPERIMENTAL GERONTOLOGY
• 影响因子: 3.9
• 作者: Hwang, Moon-Hyon;Yoo, Jeung-Ki;Luttrell, Meredith;Kim, Han-Kyul;Meade, Thomas H.;English, Mark;Nichols, Wilmer W.;Christou, Demetra D.
• 通讯作者: Christou, Demetra D.

Higher levels of adiponectin in vascular endothelial cells are associated with greater brachial artery flow-mediated dilation in older adults.

血管内皮细胞中较高水平的脂联素与老年人更大的肱动脉血流介导的扩张有关。

• DOI: 10.1016/j.exger.2014.12.018
• 发表时间: 2015
• 期刊: Experimental gerontology
• 影响因子: 3.9
• 作者: Yoo,Jeung-Ki;Hwang,Moon-Hyon;Luttrell,MeredithJ;Kim,Han-Kyul;Meade,ThomasH;English,Mark;Segal,MarkS;Christou,DemetraD
• 通讯作者: Christou,DemetraD