Obesity, vascular inflammation, and immune cell activation in prehypertension

描述（由申请人提供）：高血压（HTN）影响超过5000万美国人，并与中风和动脉粥样硬化的风险显著增加有关。第七届高血压预防、检测、评估和治疗国家联合委员会（JNC 7，2003）报告称，即使血压（BP）轻度高于正常水平，即使低于高血压范围，也可能成为心血管疾病（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50%的成年人群），并与未来CVD增加相关。然而，文献在很大程度上缺乏对血管生物学过程的关注，而血管生物学过程可能是前HTN引起的CVD风险增加的基础。此外，尽管大量流行病学证据表明BMI升高与前高血压相关，但肥胖在多大程度上导致高血压前个体的血管炎症、功能障碍和免疫细胞活化仍知之甚少。考虑到肥胖本身也与炎症有关，这些共存的疾病可能协同导致前HTN患者的血管健康恶化。本研究的首要目的是调查肥胖水平与前HTN中血管炎症和功能障碍之间的关联程度和性质。我们拟研究1）血管内皮功能障碍，2）血管炎症，和3）免疫细胞活化在不同程度的肥胖的高血压前期个体。我们将研究18 - 55岁未服用降压药物的高血压前期患者（N=200）和血压正常的患者（N=100）作为对照组。我们将检查他们的肥胖（DEXA和腰围的体脂百分比）。将通过以下方式研究血管内皮中协调的生物学事件的全面情况：将通过血流介导的肱动脉扩张评估血管功能障碍。我们将通过评估内皮素-1、可溶性内皮细胞粘附分子（CAM）、血浆炎性细胞因子、免疫细胞上的CAM表达、抗原刺激后的细胞因子产生细胞和中性粒细胞氧化爆发的水平来检查血管炎症和免疫细胞活化，不仅在休息时，而且在对心理和身体压力的反应中。标准化运动挑战和特里尔社会应激试验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应激范式。我们还将在2-2.5年内跟踪一部分受试者的体重、血压和炎症变化，以收集宝贵的试点数据，用于后续资助计划。研究肥胖对preHTN血管健康的影响程度以及脂肪因子的作用将为肥胖相关的preHTN所带来的血管损伤很可能是未来CVD的桥梁提供证据。这项研究的结果将是一个后续的纵向研究的基础上，实施行为干预，以减少肥胖和影响更精确的血管炎症通路的前HTN。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。我们建议调查肥胖在多大程度上有助于血管炎症，这可能是高血压前期个体未来发展为高血压和CVD的基础。肥胖相关高血压前期的基础血管病理学研究将对公共卫生产生重大影响，因为它为减少肥胖以预防高血压提供了行为改变的必要性证据，并提供了肥胖对免疫和血管生物学贡献的机制性理解（“从实验室到社区，超越床边”）。

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").