Vascular Endothelial Dysfunction in Older Adults: Dietary Sodium Restriction

描述(由申请者提供)：目标和健康相关：这项NRSA博士前提案寻求在新兴的生物医学重要领域“血管老化”的研究事业发展的支持。候选人雅布朗斯基的职业目标是成为转化研究的独立研究员，专注于人类血管衰老的调节机制，以及防止或逆转血管衰老的干预措施。该研究项目对心血管疾病的预防具有重要的临床意义，因为血管老化是心血管疾病的主要危险因素。研究项目：本项目将确定饮食钠限制(DSR)改善血管内皮功能的效果，血管内皮功能是血管老化的关键表现，通过内皮依赖性扩张(EDD)进行评估。EDD下降是动脉粥样硬化和心血管事件的预测指标。增龄和收缩压(SBP)升高会显著降低EDD。所涉及的因素尚不完全清楚，但饮食中的钠摄入量可能与此有关。动脉血压对盐的敏感性随着年龄的增长而增加，高盐摄入量与血管功能障碍有关。最近，我们的实验室证明，DSR改善了SBP升高的中老年人(MA/O)的颈动脉顺应性。然而，DSR对改善这一组EDD的疗效尚不清楚。为了解决这一问题，将在正常和低钠饮食条件下对SBP升高的MA/0进行研究(随机、双盲、安慰剂对照交叉设计)。DSR对EDD的影响将通过臂动脉血流介导的扩张(FMD)和前臂血流(FBF)对臂内注射乙酰胆碱(ACh)的反应来评估。四氢生物蝶呤(BH4)是内皮一氧化氮合酶(ENOS)合成NO的关键辅助因子，其降低氧化应激、增加一氧化氮(NO)生物利用度和生物活性的潜在机制也将被确定。通过对人外周血单个核细胞(PBMCs)和血管内皮细胞分析的潜在介质蛋白表达的测量，可以深入了解DSR引起EDD变化的细胞和分子机制。拟议的研究项目具有重要的公共卫生意义，因为心血管疾病仍然是美国疾病和死亡的主要原因。马萨诸塞州成年人患心血管疾病的风险增加。因此，确定生活方式干预在SBP升高的MA/O中恢复EDD的有效性和涉及的综合生理机制是临床上的当务之急，特别是考虑到对未来越来越多的老年人的预测。最后，该研究项目和培训计划将为研究职业生涯的发展提供一个出色的平台。

DESCRIPTION (provided by applicant): Goals and Health Relatedness: This predoctoral NRSA proposal seeks support for research career development in the emerging, biomedically important field of "vascular aging." The career goal of the candidate, Ms. Jablonski, is to become an independent investigator in translational research focusing on the mechanisms mediating vascular aging in humans and interventions that prevent or reverse vascular aging. The proposed research project has important clinical implications for the prevention of cardiovascular diseases (CVD) because vascular aging is a major risk factor for CVD. Research Project: This project will determine the efficacy of dietary sodium restriction (DSR) to improve vascular endothelial function, a key expression of vascular aging, as assessed by endothelium-dependent dilation (EDD). Declines in EDD are predictive of atherosclerosis and CVD events. Aging and increased systolic blood pressure (SBP) markedly reduce EDD. The factors implicated are incompletely understood, but dietary sodium intake may be involved. Arterial blood pressure sensitivity to salt increases with age and high salt intake is associated with vascular dysfunction. Recently our laboratory demonstrated that DSR improves carotid artery compliance in middle-aged and older adults (MA/O) with elevated SBP. However, the efficacy of DSR for improving EDD in this group is unknown. To address this issue, MA/0 with elevated SBP will be studied under conditions of normal and low sodium diet (randomized, double-blind, placebo controlled cross-over design). The influence of DSR on EDD will be evaluated using brachial artery flow-mediated dilation (FMD) and the forearm blood flow (FBF) response to an intrabrachial infusion of acetylcholine (ACh). The potential mechanistic roles of reductions in oxidative stress and increases in nitric oxide (NO) bioavailability and bioactivity of tetrahydrobiopterin (BH4), a critical cofactor for NO synthesis by endothelial NO synthase (eNOS), also will be determined. Insight into the cellular and molecular mechanisms involved in changes in EDD with DSR will be gained from measurements of protein expression of potential mediators analyzed from human peripheral blood mononuclear cells (PBMCs) and vascular endothelial cells. The proposed research project has important public health relevance, as CVD remains a/the leading cause of illness and death in the U.S. MA/O adults are at increased risk of CVD. As such, establishing the efficacy of lifestyle interventions that restore EDD in MA/O with elevated SBP and the integrative physiological mechanisms involved are clinically imperative, particularly given projections for the increasing number of older adults in the future. Finally, this research project and training plan will provide an outstanding platform for research career development.