Vascular Endothelial Dysfunction in Older Adults: Dietary Sodium Restriction

描述（由申请人提供）：目标和健康相关性：这个博士前NRSA的建议寻求在新兴的，生物医学上重要的领域“血管老化”的研究职业发展的支持。Jablonski女士的职业目标是成为转化研究的独立研究者，专注于介导人类血管衰老的机制以及预防或逆转血管衰老的干预措施。拟议的研究项目对预防心血管疾病（CVD）具有重要的临床意义，因为血管老化是CVD的主要危险因素。研究项目：该项目将确定饮食钠限制（DSR）改善血管内皮功能的有效性，血管内皮功能是血管老化的关键表现，通过内皮依赖性舒张（EDD）进行评估。EDD的下降可预测动脉粥样硬化和CVD事件。衰老和收缩压（SBP）升高显著降低EDD。所涉及的因素还不完全清楚，但饮食中的钠摄入可能涉及。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改善中老年人（MA/O）血压升高的颈动脉顺应性。然而，DSR改善该组EDD的功效尚不清楚。为了解决这一问题，将在正常和低钠饮食条件下研究SBP升高的MA/0（随机、双盲、安慰剂对照交叉设计）。将使用肱动脉血流介导的扩张（FMD）和前臂血流（FBF）对臂内输注乙酰胆碱（ACh）的反应来评价DSR对EDD的影响。还将确定减少氧化应激和增加一氧化氮（NO）的生物利用度和四氢生物蝶呤（BH 4）的生物活性的潜在机制作用，四氢生物蝶呤（BH 4）是内皮NO合酶（eNOS）合成NO的关键辅因子。深入了解EDD与DSR的变化所涉及的细胞和分子机制，将获得从人外周血单核细胞（PBMC）和血管内皮细胞分析的潜在介质的蛋白质表达的测量。拟议的研究项目具有重要的公共卫生相关性，因为CVD仍然是美国MA/O成年人CVD风险增加的主要疾病和死亡原因。因此，建立生活方式干预的有效性，恢复EDD在MA/O与SBP升高和综合生理机制涉及的临床上是必要的，特别是考虑到未来老年人的数量不断增加的预测。最后，本研究计画及训练计画将提供一个优秀的研究事业发展平台。

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.