Role of obesity on vascular inflammation and immune cell activation in prehyperte

描述（由申请人提供）：高血压（HTN）影响超过5000万美国人，并与卒中和动脉粥样硬化风险显著增加相关。第七届全国高血压预防、检测、评估和治疗联合委员会（JNC 7,2003）报道，即使血压（BP）轻微高于正常水平，即使低于高血压范围，也可能是心血管疾病（CVD）的危险因素，并将其命名为“高血压前期”。从那时起，高血压前期（preHTN）引起了相当大的关注，许多大型人群研究报告了其高患病率（高达成人人口的50%）并与未来心血管疾病的增加有关。然而，文献在很大程度上缺乏对血管生物学过程的关注，这些过程可能是preHTN引起的心血管疾病风险增加的基础。此外，尽管有大量流行病学证据表明高BMI和preHTN有关，但对于肥胖在高血压前期个体中对血管炎症、功能障碍和免疫细胞激活的影响程度知之甚少。鉴于肥胖本身也与炎症有关，这些共存的条件可能协同导致preHTN患者血管健康恶化。该研究的主要目的是研究preHTN中肥胖水平与血管炎症和功能障碍之间关系的程度和性质。我们建议研究1)血管内皮功能障碍，2)血管炎症，以及3)不同程度肥胖的高血压前期个体的免疫细胞激活。我们将研究18 - 55岁未服用降压药的高血压前期个体（N=200）和正常个体（N=100）作为对照组。我们将检查他们的肥胖（体脂百分比通过DEXA和腰围）。血管内皮中精心安排的生物事件的全面图景将通过以下方式进行调查：血管功能障碍将通过血流介导的肱动脉扩张来评估。我们将通过评估以下水平来检查血管炎症和免疫细胞激活：内皮素-1、可溶性内皮细胞粘附分子（CAM）、血浆炎症细胞因子、免疫细胞上的CAM表达、抗原刺激下的细胞因子产生细胞和中性粒细胞氧化爆发，不仅在休息时，而且在心理和生理应激源下。标准化运动挑战和特里尔社会压力测试是研究神经内分泌激活下免疫和心血管系统反应的可靠和强大的压力范式。我们还将对一部分受试者的体重、血压和炎症变化进行2-2.5年的随访，为后续拨款提案收集宝贵的试点数据。研究肥胖在preHTN中对血管健康的影响程度以及脂肪因子的作用，将为肥胖相关preHTN带来的血管损伤可能是未来心血管疾病的桥梁提供证据。本研究的发现将成为后续纵向研究的基础，以实施行为干预来减少肥胖，并影响preHTN中更精确的血管炎症途径。公共卫生相关性：高血压前期被认为是心血管疾病（CVD）的危险因素，但对高血压“前奏”的血管生物学知之甚少。我们建议研究肥胖对血管炎症的影响程度，这可能是高血压前期个体高血压和心血管疾病未来发展的基础。这项关于肥胖相关高血压前期的潜在血管病理学的研究将通过提供行为改变的必要性来减少肥胖以预防高血压，并通过提供肥胖对免疫和血管生物学贡献的机制理解（“从实验室到社区，超越床边”），对公共卫生产生重大影响。

DESCRIPTION (provided by applicant): Hypertension (HTN) affects more than 50 million Americans and is associated with significantly increased risk for stroke and atherosclerosis. The 7th Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7, 2003) reported that even a mild elevation of blood pressure (BP) above normal, even if it is below the hypertensive range, can be a risk factor for cardiovascular disease (CVD) and named it "prehypertension". Prehypertension (preHTN) has drawn considerable attention since then, and a number of large population studies have reported its high prevalence (up to 50% of the adult population) and association with increased future CVD. However, the literature largely lacks a focus on the vascular biology processes that may underlie the increased risk for CVD posed by preHTN. Furthermore, little is known on the degree to which obesity contributes to vascular inflammation and dysfunction and immune cell activation among prehypertensive individuals, despite the wealth of epidemiological evidence linking higher BMI and preHTN. Given that obesity itself is also associated with inflammation, these co-existing conditions may synergistically lead to worsening of vascular health in individuals with preHTN. The overarching aim of the study is to investigate the degree and nature of the association between the level of adiposity and vascular inflammation and dysfunction in preHTN. We propose to study 1) vascular endothelial dysfunction, 2) vascular inflammation, and 3) immune cell activation in prehypertensive individuals with varying degrees of adiposity. We will study 18 to 55 year-old prehypertensive individuals (N=200) who are not taking anti-hypertensive medications and normotensive individuals (N=100) as a control group. We will examine their adiposity (% body fat by DEXA and waist circumference). A comprehensive picture of orchestrated biological events in the vascular endothelium will be investigated by following: vascular dysfunction will be assessed by flow mediated brachial artery dilation. We will examine vascular inflammation and immune cell activation by assessing levels of: endothelin-1, soluble endothelial cell adhesion molecules (CAM), plasma inflammatory cytokines, CAM expression on immune cells, cytokine producing cells upon antigen stimulation, and neutrophil oxidative burst, not only at rest but also in response to psychological and physical stressors. A standardized exercise challenge and Trier Social Stress Test are reliable and robust stress paradigms to investigate immune and cardiovascular system responses under neuroendocrine activation. We will also follow weight, BP, and inflammation changes in a subset of subjects for 2-2.5 years to gather invaluable pilot data for a follow-up grant proposal. Investigating the degree to which adiposity contributes to vascular health in preHTN and the role of adipokines will provide the evidence that the vascular damages brought by obesity-related preHTN may well be the bridge to future CVD. Findings of this study will be a basis for a follow-up longitudinal study to implement behavioral interventions to reduce adiposity and to influence more pinpointed vascular inflammatory pathways in preHTN. PUBLIC HEALTH RELEVANCE: Prehypertension is recognized as a risk factor for cardiovascular disease (CVD), but little is known of the vascular biology of this "prelude" to hypertension. We propose to investigate the degree to which adiposity contributes to vascular inflammation that may underlie future development of hypertension and CVD in prehypertensive individuals. This study of underlying vascular pathology in obesity-related prehypertension will have a significant public health impact by providing the evidence for the need for behavioral modifications to reduce obesity for the prevention of hypertension and by providing a mechanistic understanding of the contributions of obesity to immune and vascular biology ("bench-to-community, beyond bedside").