Social Environment, Hyperlipidemia, Inflammation & Atherosclerosis in WHHL Rabbit

社会环境、高脂血症、炎症

• 批准号: 7248205
• 负责人: PHILIP M MCCABE
• 金额: $ 41.59万
• 依托单位: UNIVERSITY OF MIAMI CORAL GABLES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7248205
• 关键词: Agonistic Behavior; Angiotensin Receptor; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Aorta; Arterial Fatty Streak; Atherosclerosis; Behavioral; Blood Vessels; C-reactive protein; Cells; Chronic; Data; Development; Disease Progression; Disease model; Emotional Stress; Foam Cells; Genetic Models; Housing; Hyperinsulinism; Hyperlipidemia; Inflammation; Inflammatory; Laboratories; Lesion; Location; Measures; Modeling; NAD(P)H oxidase; Necrosis; Oryctolagus cuniculus; Oxidative Stress; Oxytocin; Plasma; Relative (related person); Research; Risk Factors; Role; Severity of illness; Social Environment; Sympathetic Nervous System; Time; Weight; base; biobehavior; calcification; cytokine; receptor; sedentary; size; social group

The proposed research will examine the influence of social environment on hyperlipidemic, oxidative, and inflammatory mechanisms of atherosclerosis in the Watanabe Heritable Hyperlipidemic rabbit (WHHL). Previous research from our laboratory demonstrated that WHHLs allowed to maintain stable relationships, as opposed to WHHLs housed alone or subjected to unstable relationships, showed a significant decrease in the progression of atherosclerosis. An unstable social environment, characterized by agonistic behavior and emotional stress, was associated with the development of severe atherosclerotic lesions (fibrous caps, necrosis, calcification), whereas individually-caged WHHLs developed extensive lesions that were not as advanced (primarily foam cells and fatty streaks). The individually-caged WHHLs were also behaviorally sedentary, gained more weight, and were hyperinsulinemic relative to the other groups. Taken together, these findings suggest that biobehavioral factors are important in the progression of atherosclerosis, even in a predominantly genetic model of disease. Based on preliminary data, it is hypothesized that social environment differentially modulates inflammatory and oxidative stress mechanisms responsible for disease progression. Hyperlipidemia, which is common to all WHHLs, is viewed as a primary risk factor capable of directly stimulating the formation of vascular foam cells and fatty streaks. Over time, oxidative stress and inflammatory mechanisms are activated, which accelerates progression of disease, leading to more advanced lesions and vulnerable plaque. It is proposed that atherosclerosis in the Stable Social Group progresses slowly due to the antioxidant and anti-inflammatory actions of plasma oxytocin on vascular cells. In the Individually-Caged Group, it is proposed that increased vascular oxidative stress due to behavioral inactivity and hyperinsulinemia leads to rapid development of foamy, fatty lesions in vulnerable regions of the aorta. We hypothesize that the Unstable Social Group develops lesions of similar size and location to the Individually-Caged animals due to the hyperlipidemic mechanisms, however, disease severity progresses more rapidly in the Unstable WHHLs due to chronic activation of the sympathetic nervous system (SNS) which stimulates the release of proinflammatory cytokines and C-reactive protein (CRP). Therefore, the specific aims of the project are: 1.) To assess the influence of plasma oxytocin, as a function of social environment, on vascular oxidative stress, inflammation, and atherosclerosis in the WHHL model, 2.) To measure the effects of NAD(P)H oxidase antagonism, or angiotensin receptor (AT1) antagonism, on the progression of atherosclerosis as a function of social environment, and 3.) To assess the role of proinflammatory cytokines and CRP on disease progression as a function of social environment, and the effects of SNS antagonism on these inflammatory mechanisms.

拟议的研究将探讨社会环境对高脂血症、氧化和代谢的影响。 渡边遗传性高脂血症兔（WHHL）动脉粥样硬化的炎症机制。 我们实验室之前的研究表明，WHHL 可以维持稳定的关系，因为 与单独居住或关系不稳定的 WHHL 相比，显示出显着下降 动脉粥样硬化的进展。不稳定的社会环境，以竞争行为为特征 情绪压力与严重动脉粥样硬化病变（纤维帽、 坏死、钙化），而单独笼养的 WHHL 则出现了广泛的病变，但这些病变并不像单独笼养的 WHHL 那样。 高级（主要是泡沫细胞和脂肪条纹）。单独笼养的 WHHL 在行为上也受到影响 与其他组相比，久坐、体重增加、胰岛素水平升高。综合起来， 这些发现表明生物行为因素在动脉粥样硬化的进展中很重要，即使在 疾病的主要遗传模型。根据初步数据，假设社会 环境差异调节导致疾病的炎症和氧化应激机制 进展。高脂血症是所有 WHHL 的常见现象，被视为主要危险因素 直接刺激血管泡沫细胞和脂肪纹的形成。随着时间的推移，氧化应激和 炎症机制被激活，加速疾病进展，导致更多 晚期病变和易损斑块。有人提出，稳定社会群体中的动脉粥样硬化 由于血浆催产素对血管细胞的抗氧化和抗炎作用，进展缓慢。 在单独笼养组中，有人提出，行为导致的血管氧化应激增加 缺乏活动和高胰岛素血症会导致身体脆弱区域迅速出现泡沫状脂肪病变 主动脉。我们假设不稳定的社会群体会产生与社会群体相似大小和位置的病变。 然而，由于高脂血症机制，单独笼养动物，疾病严重程度会加重 由于交感神经系统 (SNS) 的慢性激活，在不稳定的 WHHL 中速度更快 它刺激促炎细胞因子和 C 反应蛋白 (CRP) 的释放。因此， 该项目的具体目标是： 1.) 评估血浆催产素作为社会功能的影响 环境对 WHHL 模型中血管氧化应激、炎症和动脉粥样硬化的影响，2.) 测量 NAD(P)H 氧化酶拮抗作用或血管紧张素受体 (AT1) 拮抗作用对 动脉粥样硬化的进展作为社会环境的函数，以及 3.) 评估 促炎细胞因子和 CRP 作为社会环境的函数对疾病进展的影响，以及 SNS 拮抗作用对这些炎症机制的影响。