Vascular Endothelial Dysfunction in Older Adults: Dietary Sodium Restriction

描述（由申请人提供）：目标和健康关系：此博士前NRSA提案旨在支持新兴的生物医学重要领域“血管衰老”的研究事业发展。雅布隆斯基女士的职业目标是成为转化研究的独立研究者，专注于调节人类血管衰老的机制和预防或逆转血管衰老的干预措施。由于血管老化是心血管疾病的主要危险因素，该研究项目对心血管疾病的预防具有重要的临床意义。研究项目：该项目将确定饮食钠限制（DSR）对改善血管内皮功能的功效，血管内皮功能是血管衰老的关键表达，通过内皮依赖性扩张（EDD）进行评估。EDD的下降预示着动脉粥样硬化和心血管疾病的发生。衰老和收缩压（SBP）升高可显著降低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，高盐摄入与血管功能障碍有关。最近，我们的实验室证明，DSR可以改善收缩压升高的中老年人（MA/O）的颈动脉顺应性。然而，DSR对该组EDD的改善效果尚不清楚。为了解决这个问题，将在正常和低钠饮食条件下研究MA/0升高的收缩压（随机、双盲、安慰剂对照交叉设计）。DSR对EDD的影响将通过肱动脉血流介导扩张（FMD）和前臂血流量（FBF）对臂内输注乙酰胆碱（ACh）的反应来评估。四氢生物蝶呤（BH4）是内皮NO合成酶（eNOS）合成NO的关键辅助因子，其氧化应激减少和一氧化氮（NO）生物利用度和生物活性的增加的潜在机制作用也将被确定。通过对人外周血单核细胞（PBMCs）和血管内皮细胞中潜在介质的蛋白表达进行分析，可以深入了解EDD伴DSR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相关性，因为心血管疾病仍然是美国MA/O成年人疾病和死亡的主要原因，心血管疾病的风险增加。因此，确定生活方式干预的有效性，恢复收缩压升高的MA/O患者的EDD，以及相关的综合生理机制，在临床上是必要的，特别是考虑到未来老年人数量的增加。最后，该研究项目和培训计划将为研究职业发展提供一个优秀的平台。

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.