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

描述(由申请人提供)：高血压(HTN)影响着5000多万美国人，并与中风和动脉粥样硬化的风险显著增加有关。第七届全国预防、检测、评估和治疗高血压联合委员会(JNC 7,2003)报告称，即使血压(BP)略高于正常水平，即使它低于高血压范围，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”。自那时以来，高血压前期(PreHTN)引起了相当大的关注，许多大规模人口研究报告了其高患病率(高达成年人口的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HTN前病变引起的心血管疾病风险增加的基础。此外，尽管有丰富的流行病学证据将高BMI和高血压前期联系在一起，但对于肥胖在多大程度上导致高血压前期患者的血管炎症和功能障碍以及免疫细胞激活，人们知之甚少。考虑到肥胖本身也与炎症有关，这些共存的疾病可能会协同导致HTN前期患者血管健康恶化。这项研究的主要目的是调查肥胖水平与HTN前期患者血管炎症和功能障碍之间的关系的程度和性质。我们建议研究1)血管内皮功能障碍，2)血管炎症，3)不同程度肥胖的高血压前期个体的免疫细胞激活。我们将研究未服用降压药的18至55岁高血压前期个体(N=200)和血压正常的个体(N=100)作为对照组。我们将检查他们的肥胖度(DEXA和腰围的体脂百分比)。血管内皮细胞中协调的生物事件的全面图景将通过以下方式进行研究：血管功能障碍将通过血流介导的臂动脉扩张来评估。我们将通过评估内皮素-1、可溶性内皮细胞黏附分子(CAM)、血浆炎性细胞因子、免疫细胞上CAM的表达、抗原刺激下的细胞因子产生细胞以及中性粒细胞氧化爆发的水平来检测血管炎症和免疫细胞激活，这些水平不仅在静息状态下，而且在心理和生理应激源的反应中也是如此。标准化运动挑战和Trier社会压力测试是研究神经内分泌激活下的免疫和心血管系统反应的可靠和稳健的应激范例。我们还将在2-2.5年内跟踪受试者子集的体重、血压和炎症变化，为后续拨款提案收集宝贵的试点数据。研究肥胖对前HTN患者血管健康的贡献程度以及脂肪因子的作用将为肥胖相关的前HTN带来的血管损害提供证据，很可能是通向未来CVD的桥梁。这项研究的发现将为后续的纵向研究提供基础，以实施行为干预以减少肥胖，并影响更准确的HTN前血管炎症通路。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，但对高血压的这一“前奏”的血管生物学知之甚少。我们建议调查肥胖对血管炎症的贡献程度，这可能是高血压前期个体未来高血压和心血管疾病发展的基础。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对公众健康产生重大影响，因为它提供了证据，证明需要通过行为改变来减少肥胖，以预防高血压，并提供对肥胖对免疫和血管生物学的贡献的机械性理解(“病床到社区，床边以外”)。

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").