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）：代谢综合征由代谢和血管来源的相关风险因素的聚集定义，是影响约4700万美国居民的主要公共卫生问题。代谢综合征的患病率在中年和老年人中尤其高，在50岁以上的男性和女性中约有44%发生。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关键早期事件，在代谢综合征患者和老年人中很常见。然而，对这种损害的机制知之甚少。这项研究将确定盐皮质激素受体的阻断是否能改善患有代谢综合征的中老年人的血管内皮依赖性舒张，这是一种临床相关的内皮功能标志物。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。我们的工作假设是盐皮质激素受体阻滞剂将导致改善内皮依赖性舒张。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）后，一次在安慰剂（即，控制条件）。将使用高分辨率多普勒超声无创测定内皮依赖性舒张（肱动脉血流介导的舒张）和内皮非依赖性舒张（舌下含服硝酸甘油后肱动脉舒张）。深入了解介导血管内皮功能受损和盐皮质激素受体阻断后的改善的分子机制，将获得使用一种新的翻译研究技术，收集人内皮细胞和确定蛋白质表达的促动脉粥样硬化和抗动脉粥样硬化因子通过定量免疫荧光。还将在血液中测定氧化应激和炎症的全身性生物标志物。预期的结果应显着扩展我们目前的理解的综合（全身分子）的生理机制血管内皮功能障碍的老化和代谢综合征。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，定义为多种心血管危险因素的共存，是一个主要的公共卫生问题。代谢综合征的发生率在中年和老年人中尤其高。这项研究将在患有代谢综合征的中老年人中调查盐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。

项目成果

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

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.