Social Environment, Hyperlipidemia, Inflammation & Atherosclerosis in WHHL Rabbit

社会环境、高脂血症、炎症

• 批准号: 8073989
• 负责人: PHILIP M MCCABE
• 金额: $ 32.62万
• 依托单位: UNIVERSITY OF MIAMI CORAL GABLES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8073989
• 关键词: Agonistic Behavior; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Aorta; Arterial Fatty Streak; Atherosclerosis; Behavioral; Blood Vessels; C-reactive protein; Cells; Chronic; Data; Development; Disease; Disease Progression; Emotional Stress; Foam Cells; Genetic Models; Housing; Hyperinsulinism; Hyperlipidemia; Inflammation; Inflammatory; Laboratories; Lesion; Location; Measures; Modeling; Necrosis; Oryctolagus cuniculus; Oxidases; Oxidative Stress; Oxytocin; Plasma; Receptor, Angiotensin, Type 1; Relative (related person); Research; Risk Factors; Role; Severity of illness; Social Environment; Sympathetic Nervous System; Time; Weight; base; biobehavior; calcification; cytokine; receptor; sedentary; 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.

拟议的研究将研究社会环境对高脂症，氧化和 Watanabe遗传性高脂兔（WHHL）中动脉粥样硬化的炎症机制。 我们实验室的先前研究表明，WHLS允许保持稳定的关系，因为 反对单独容纳或存在不稳定关系的WHHL，显示出显着下降 动脉粥样硬化的进展。一个不稳定的社会环境，其特征是激动行为和 情绪压力与严重的动脉粥样硬化病变的发展有关（纤维帽， 坏死性，钙化），而单独截断的WHHL发生了广泛的病变 高级（主要是泡沫细胞和脂肪条纹）。单独割礼的WHHL在行为上也是 相对于其他组，久坐的重量增加，并且具有高胰岛素。在一起， 这些发现表明，即使在 主要是疾病的遗传模型。基于初步数据，可以假设社会 环境差异调节了负责疾病的炎症和氧化应激机制 进展。所有WHHL常见的高脂血症被视为能够的主要危险因素 直接刺激血管泡沫细胞和脂肪条纹的形成。随着时间的流逝，氧化应激和 激活炎症机制，加速疾病的进展，导致更多 高级病变和脆弱的牌匾。有人提出，稳定社会群体的动脉粥样硬化 由于血浆催产素对血管细胞的抗氧化剂和抗炎作用而缓慢进展。 在单独截断的组中，有人提出增加了由于行为而增加的血管氧化应激 不活跃和高胰岛素血症会导致泡沫状，弱势损害的脆弱区域的快速发展 主动脉。我们假设不稳定的社会群体发展出与 但是，由于高脂血症机制，单独割伤的动物，疾病的严重程度进展 由于交感神经系统（SNS）的长期激活，在不稳定的WHHL中更快 刺激促炎细胞因子和C反应蛋白（CRP）的释放。因此， 该项目的具体目的是：1。）评估血浆催产素的影响，作为社会的函数 WHHL模型中的血管氧化应激，炎症和动脉粥样硬化的环境，2。） 测量NAD（P）H氧化酶拮抗或血管紧张素受体（AT1）拮抗作用对拮抗作用的影响 动脉粥样硬化作为社会环境的函数的进展，3。）评估 促炎性细胞因子和疾病进展的CRP随着社会环境的函数，以及 SNS拮抗对这些炎症机制的影响。