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

肥胖对高血压前期血管炎症和免疫细胞激活的作用

• 批准号: 7590157
• 负责人: Suzi Hong
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7590157
• 关键词: Adult; Affect; American; Antigens; Antihypertensive Agents; Applications Grants; Atherosclerosis; Attention; Behavior Therapy; Biological; Biology; Blood Pressure; Blood Vessels; Body fat; Boxing; Caliber; Cardiovascular Diseases; Cardiovascular system; Cell Adhesion Molecules; Cells; Clinical; Communities; Control Groups; DEXA; Data; Detection; Development; Endothelial Cells; Endothelin-1; Epidemiology; Evaluation; Event; Exercise; Functional disorder; Future; Health; High Prevalence; Hypertension; ITGAM gene; Immune; Immune Cell Activation; Immune system; Individual; Inflammation; Inflammatory; Interleukin-6; Investigation; Joints; Laboratories; Lead; Leptin; Leukocytes; Light; Link; Literature; Longitudinal Studies; Mediating; Modeling; Names; Nature; Neurosecretory Systems; Neutrophil Activation; Obesity; Pathology; Pathway interactions; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma; Population; Population Study; Prevention; Process; Production; Public Health; Reporting; Respiratory Burst; Rest; Risk; Risk Factors; Role; Spottings; Staging; Stress; Stress Tests; Stroke; T-Lymphocyte; TNF gene; Trier Social Stress Test; Vascular Endothelium; Weight; adipokines; adiponectin; base; brachial artery; cardiovascular disorder risk; cytokine; follow-up; inflammatory marker; monocyte; neutrophil; normotensive; novel; obesity prevention; psychologic; public health relevance; resistin; response; stressor; vascular endothelial dysfunction; vascular inflammation; waist circumference

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").

描述（由申请人提供）：高血压（HTN）影响超过5000万美国人，并且与中风和动脉粥样硬化的风险显着增加有关。第七届全国预防，检测，评估和治疗高血压的联合委员会（JNC 7，2003）报告说，即使低于正常的血压（BP）轻度升高，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“预替代性”。自那时以来，预期前（PREHTN）引起了很大的关注，许多大型人口研究报告了其高患病率（占成年人口的50％），并与未来CVD的增加相关。但是，文献在很大程度上缺乏关注的血管生物学过程，这些过程可能是PREHTN带来的CVD风险增加的基础。此外，尽管有大量的流行病学证据与较高的BMI和PREHTN联系在一起，但肥胖对血管炎症，功能障碍和免疫细胞激活的程度知之甚少。鉴于肥胖本身也与炎症有关，因此这些共存的疾病可能会导致PREHTN患者的血管健康恶化。该研究的总体目的是研究PREHTN的肥胖水平与血管炎症和功能障碍之间关联的程度和性质。我们建议研究1）血管内皮功能障碍，2）血管炎症和3）具有不同程度的肥胖性的高血压前个体的免疫细胞活化。我们将研究18至55岁的年轻人（n = 200），他们没有服用抗高血压药物和正常的人（n = 100）作为对照组。我们将检查它们的肥胖性（Dexa和腰围的体内脂肪％）。将通过以下研究研究血管内皮中精心策划的生物事件的全面图片：血管功能障碍将通过流动介导的臂动脉扩张来评估。我们将通过评估：内皮蛋白-1的水平，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，在抗原刺激上产生细胞的细胞因子对抗原刺激的细胞产生细胞，不仅在心理和物理方面的响应不仅在心理方面。标准化的运动挑战和Trier社会压力测试是可靠且强大的压力范式，以研究神经内分泌激活下的免疫和心血管系统反应。我们还将遵循2 - 2。5年的主体子集的体重，BP和炎症变化，以收集宝贵的试点数据以进行后续拨款提案。调查肥胖对PREHTN的血管健康的程度以及脂肪因子的作用将提供证据，证明与肥胖相关的PreHTN造成的血管损害很可能是通往未来CVD的桥梁。这项研究的结果将是进行后续纵向研究的基础，以实施行为干预措施，以减少肥胖性并影响PREHTN中更精确的血管炎症途径。公共卫生相关性：预元被公认为是心血管疾病（CVD）的危险因素，但对这种“前奏”的血管生物学对高血压的血管生物学知之甚少。我们建议调查肥胖对血管炎症的促进，这可能是高血压前个体中高血压和CVD的未来发展的基础。这项研究与肥胖相关的近代前期潜在的血管病理学的研究将对公共卫生的影响产生重大的影响，这是通过提供行为修改的证据，以减少预防高血压的肥胖症，并通过对肥胖对免疫和血管生物学的贡献的机械理解（超越床头层之外”）。