Social Environment, Sympathetic Nervous System & Atherosclerosis in WHHL Rabbits

描述（由申请人提供）：拟议的研究将检查社会/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，分子介质和临床疾病进展之间的机制联系。这将通过使用Watanabe遗传性高脂血症兔（WHHL）来实现，这是一种以高脂血症和严重动脉粥样硬化为特征的遗传动物模型。我们已经证明，社会环境深刻地影响疾病的过程中WHHL，这样的动物在稳定的关系与同窝，而不是WHHL在不稳定的社会条件或社会隔离，显示出显着减少动脉粥样硬化的进展。不稳定的社会环境，其特征是好斗行为和情绪压力，与严重的、晚期动脉粥样硬化病变的发展相关。这些发现表明，生物行为因素在动脉粥样硬化的进展中是重要的，即使在具有强遗传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介质尚不清楚。交感神经系统（SNS）是社会环境与疾病联系的最可能的介质之一，在初步工作中，我们观察到动脉粥样硬化血管组织中存在SNS过度神经支配。这种慢性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。拟议的工作将检查是否发生这种SNS重塑响应社会环境或当地疾病的存在。我们还将评估是否阻止这种SNS神经支配过度减弱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）。检查WHHL与正常血脂对照兔（新西兰白色; NZW）随时间变化的血管组织的SNS神经支配密度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.）检查WHHL与NZW中其他外周组织的SNS神经支配密度作为社会环境的函数，以及2.）在药理学拮抗NGF的靶受体TrkA后，量化WHHL中的血管SNS神经支配密度、炎症和动脉粥样硬化。拟议的研究代表了一种新的方法来了解已知的风险因素（例如，高脂血症）可能与行为变量相互作用，导致疾病的加重或减轻。这种类型的SNS神经元可塑性，以及由此产生的增强的血管炎症/氧化应激，可能代表心血管疾病的行为和/或药物治疗的干预目标。

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.