Endothelial Dysfunction in Older Adult Humans with the Metabolic Syndrome

描述(由申请人提供)：代谢综合征，由代谢和血管起源的相互关联的风险因素聚集而成，是影响约4700万美国居民的主要公共健康问题。代谢综合征在中老年人中的患病率尤其高，50岁以上的男性和女性中约有44%的人患有代谢综合征。衰老和代谢综合征与心血管疾病和死亡的风险增加有关。动脉粥样硬化是心血管疾病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制中的关键早期事件，在代谢综合征患者中很常见，在老年人中也是如此。然而，造成这种损害的机制却知之甚少。这项拟议的研究将确定阻断盐皮质激素受体是否能改善患有代谢综合征的中老年患者的血管内皮依赖性扩张，这是一种临床上与内皮功能相关的标志。我们还将研究氧化应激和炎症在调节这些有益效应中的作用。我们的工作假设是，阻断盐皮质激素受体将导致内皮依赖性扩张的改善。这一改善将与氧化应激和炎症的生物标记物的进一步减少有关。这些生物标志物的基线水平升高的个人将在封锁后体验到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，一次是在盐皮质激素受体阻滞剂(Eplerenone)之后，一次是在安慰剂(即对照条件)之后。高分辨率双功超声将无创性地测定内皮依赖性扩张(肱动脉血流介导的扩张)和非内皮依赖性扩张(舌下含服硝酸甘油后的肱动脉扩张)。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表达的新的翻译研究技术，将深入了解介导血管内皮细胞功能受损和盐皮质激素受体阻断后改善的分子机制。氧化应激和炎症的全身性生物标记物也将在血液中确定。预期的结果将极大地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整合(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：由多种心血管危险因素共存定义的代谢综合征是一个重大的公共卫生问题。代谢综合征在中老年人中的发生率尤其高。这项拟议的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，血管内皮功能障碍是动脉粥样硬化发展的关键早期事件。

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.