Social Environment, Hyperlipidemia, Inflammation & Atherosclerosis in WHHL Rabbit

这项拟议的研究将考察社会环境对高脂血症、氧化和 渡边遗传性高脂血症兔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，如 与单独居住或受到不稳定关系影响的WHHL相反，显示出 动脉粥样硬化的进展。不稳定的社会环境，以争强好胜的行为和 情绪应激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出现广泛的病变，不像 高级(主要是泡沫细胞和脂肪条纹)。单独笼养的WHHL在行为上也是 久坐不动，体重增加，与其他组相比有高胰岛素血症。加在一起， 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 一种主要的疾病遗传模型。根据初步数据，假设社会 环境对致病的炎症和氧化应激机制的不同调控 进步。高脂血症，这是所有WHHL共同的，被视为能够 直接刺激血管泡沫细胞和脂肪条纹的形成。随着时间的推移，氧化应激和 炎症机制被激活，这加速了疾病的发展，导致更多 晚期病变和易损斑块。社会稳定人群中动脉粥样硬化的研究 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。 在单独笼养的组中，有人认为血管氧化应激增加是由于行为 缺乏活动和高胰岛素血症会导致心脏脆弱区域迅速形成泡沫状脂肪病变。 大动脉。我们假设，不稳定的社会群体会发展出类似于 然而，由于高脂血症的机制，单独关在笼子里的动物疾病严重程度会进展 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 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。至 测定NAD(P)H氧化酶拮抗剂或血管紧张素受体(AT1)拮抗剂对 3.动脉粥样硬化的进展与社会环境的关系。评估……的作用 促炎细胞因子和C反应蛋白作为社会环境的函数在疾病进展中的作用 SNS拮抗对上述炎症机制的影响。

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.