ENVIRONMENT, CNS, AND ATHEROSCLEROSIS IN AN ANIMAL MODEL

描述(由申请人提供)： 我们已经证明，社会行为因素可以影响 动脉粥样硬化在遗传易感性动物模型中的进展 疾病的发展，渡边遗传性高脂血症兔 (WHHL)。研究发现，社会条件稳定，伴随而来的是 附属社会行为，减缓动脉粥样硬化病变的进展 在这些动物身上。相比之下，处于不稳定社会条件下的动物， 表现出更多的争斗行为，单独饲养的动物 严重的大动脉病变。这些数据不能完全用 静息血浆糖皮质激素、性腺类固醇、血脂水平，也不静息 心血管测量。据推测，慢性激活的细胞 交感神经系统(SNS)加速高血压的进展 动脉硬化。此外，我们还将检查中枢神经系统(CNS) 三叉神经核和下丘脑-垂体的调节机制 肾上腺皮质轴(HPA)，主要关注中枢的作用 促肾上腺皮质激素释放激素(CRH)和催产素(OT)对SNS的控制 和HPA反应。据推测，CRH在 应激行为，刺激SNS和HPA，从而加速 疾病的发展。相比之下，中央OT，已经与 更多的附属行为，可能会在稳定的社会期间缓冲有机体 通过抑制HPA轴和SNS抑制应激的条件 活动。单独饲养的动物表现出低糖皮质激素水平和 几乎没有表现出有压力的行为，但仍然有显著的发展 动脉硬化。这些久坐不动的动物比 其他人群并出现严重的高胰岛素血症，这表明 与胰岛素代谢综合征相关的因素可能特别 对这一组疾病的进展很重要。拟议中的工作 将：1)评估SNS在行为相关动脉粥样硬化中的作用 通过选择性肾上腺素能受体拮抗剂，2)确定 中枢CRH在调节SNS活性和动脉粥样硬化中的作用 通过中央给药的CRH拮抗剂的慢性社会压力，3)测量 下丘脑室旁核催产素释放的变化 慢性微透析在社会环境中的作用 确定中枢催产素在调节HPA和SNS活性中的作用， 及其与动脉粥样硬化的关系--通过中枢应用OT 拮抗剂，5)评估饮食限制或日常锻炼对 与胰岛素代谢综合征和动脉粥样硬化相关的危险因素 在单独笼养的WHHL中，以及6)检查社会的影响 环境对杂合子WHHL动脉粥样硬化的影响--替代模型 这与血脂状况和疾病进展在一个大的 人类的百分比。

DESCRIPTION (provided by applicant): We have demonstrated that social behavioral factors can influence the progression of atherosclerosis in an animal model genetically predisposed to the development of disease, the Watanabe Heritable Hyperlipidemic Rabbit (WHHL). It was found that stable social conditions, accompanied by increased affiliative social behavior, slowed the progression of atherosclerotic lesions in these animals. In contrast, animals in unstable social conditions, displaying increased agonistic behavior, and animals housed singly exhibited significant aortic pathology. These data could not be explained entirely by resting plasma glucocorticoids, gonadal steroids, lipid levels, nor resting cardiovascular measures. It is hypothesized that chronic activation of the sympathetic nervous system (SNS) accelerates the progression of atherosclerosis. In addition, we will examine Central Nervous System (CNS) mechanisms underlying the regulation of the SNS and hypothalamic pituitary adrenocortical axis (HPA), focusing primarily on the roles of central corticotropin-releasing hormone (CRH) and oxytocin (OT) in the control of SNS and HPA responses. It is hypothesized that CRH, released centrally during stressful behavior, stimulates the SNS and HPA, thereby accelerating the progression of disease. In contrast, central OT, which has been linked to increased affiliative behavior, may buffer the organism during stable social conditions from the effects of stress by inhibiting the HPA axis and SNS activity. Animals housed singly exhibited low glucocorticoid levels and showed little stressful behavior, yet still developed significant atherosclerosis. These sedentary animals gained more body weight than the other groups and developed profound hyperinsulinemia, suggesting that risk factors related to the Insulin Metabolic Syndrome may be particularly important for the progression of disease in this group. The proposed work will: 1) assess the role of the SNS in behaviorally-related atherosclerosis via selective adrenergic receptor antagonists, 2) determine the role of central CRH in the regulation of SNS activity and atherosclerosis during chronic social stress via a centrally administered CRH antagonist, 3) measure changes in the release of OT in the hypothalamic paraventricular nucleus as a function of social environment through the use of chronic microdialysis, 4) determine the role of central OT in the regulation of HPA and SNS activity, and its relationship to atherosclerosis via a centrally administered OT antagonist, 5) assess the impact of dietary restriction or daily exercise on risk factors related to the insulin metabolic syndrome and atherosclerosis and in individually-caged WHHLs, and 6) examine the influence of social environment on atherosclerosis in the heterozygous WHHL, an alternative model that more closely parallels lipid status and disease progression in a large percentage of humans.