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.
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