Social Environment, Sympathetic Nervous System & Atherosclerosis in WHHL Rabbits

描述(申请人提供)：这项拟议的研究将研究社会/情绪因素在动脉粥样硬化中的作用，并试图建立生物行为风险因素、分子介体和临床疾病进展之间的机制联系。这将通过使用渡边遗传性高脂血症兔(WHHL)来实现，WHHL是一种以高脂血症和严重动脉粥样硬化为特征的遗传性动物模型。我们已经证明，社会环境对WHHL的病程有深刻的影响，与不稳定的社会条件或社会孤立的WHHL相比，与产仔关系稳定的动物显示出动脉粥样硬化的进展显著减少。以争强好胜的行为和情绪压力为特征的不稳定的社会环境与严重的晚期动脉粥样硬化病变的发展有关。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，即使在具有强烈基因决定因素的疾病模型中也是如此。众所周知，高脂血症、炎症和氧化应激是动脉粥样硬化的近端血管机制，但将社会/情绪行为与这些疾病驱动因素联系起来的媒介尚不清楚。交感神经系统(SNS)是最有可能将社会环境与疾病联系起来的媒介之一，在前期工作中，我们观察到动脉粥样硬化的血管组织中存在SNS的过度神经支配。这种慢性的SNS结构可塑性被认为会加剧血管炎症、氧化应激和动脉粥样硬化的进展。这项拟议的工作将检验这种SNS重塑是由于社会环境的原因还是与当地疾病的存在有关。我们还将评估阻止这种SNS过度神经支配是否可以减轻血管炎症和动脉粥样硬化的进展。因此，该项目的具体目标是：1.)检测WHHL与正常血脂对照兔(新西兰白；NZW)血管组织的SNS神经支配密度随时间的变化作为社会环境的函数，并将这些差异与动脉粥样硬化的进展联系起来，1b.)研究WHHL与NZW人群其他外周组织的SNS神经支配密度与社会环境的关系。在NGF靶受体TrkA的药理拮抗作用下，对WHHL的血管SNS神经支配密度、炎症和动脉粥样硬化进行量化。这项拟议的研究代表了一种新的方法，可以理解已知的危险因素(例如高脂血症)如何与行为变量相互作用，导致疾病的恶化或减轻。这种类型的SNS神经元可塑性，以及由此导致的血管炎症/氧化应激增强，可能是心血管疾病行为和/或药物治疗的干预靶点。

DESCRIPTION (provided by applicant): The proposed research will examine the role of social/emotional factors in atherosclerosis, and attempt to establish mechanistic links among biobehavioral risk factors, molecular mediators and clinical disease progression. This will be accomplished through the use of the Watanabe Heritable Hyperlipidemic Rabbit (WHHL), a genetic animal model characterized by hyperlipidemia and severe atherosclerosis. We have demonstrated that social environment profoundly affects the course of disease in WHHLs, such that animals in stable relationships with littermates, as opposed to WHHLs in unstable social conditions or social isolation, 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, advanced atherosclerotic lesions. These findings suggest that biobehavioral factors are important in the progression of atherosclerosis, even in models of disease that have strong genetic determinants. It is well established that hyperlipidemia, inflammation and oxidative stress are the proximal vascular mechanisms in atherosclerosis, but the mediators linking social/emotional behavior to these drivers of disease are not clear. One of the most likely mediators linking social environment to disease is the sympathetic nervous system (SNS), and in preliminary work, we have observed that there is SNS hyperinnervation in atherosclerotic vascular tissue. This chronic SNS structural plasticity is proposed to exacerbate vascular inflammation, oxidative stress, and the progression of atherosclerosis. The proposed work will examine whether this SNS remodeling occurs in response to social environment or to the presence of local disease. We will also assess whether preventing this SNS hyperinnervation attenuates vascular inflammation and the progression of atherosclerosis. Therefore, the specific aims of the project are: 1a.) to examine SNS innervation density of vascular tissue in WHHLs vs normolipidemic control rabbits (New Zealand White; NZW) over time as a function of social environment, and to relate these differences to the progression of atherosclerosis, 1b.) to examine SNS innervation density of other peripheral tissue in WHHLs vs NZWs as a function of social environment, and 2.) to quantify vascular SNS innervation density, inflammation and atherosclerosis in WHHLs following pharmacological antagonism of NGF's target receptor, TrkA. The proposed research represents a novel approach to understanding how known risk factors (e.g., hyperlipidemia) may interact with behavioral variables to lead to the exacerbation or attenuation of disease. This type of SNS neuronal plasticity, and the resulting enhanced vascular inflammation/oxidative stress, may represent intervention targets for behavioral and/or pharmacological therapy in cardiovascular disease.