Social Environment, Hyperlipidemia, Inflammation & Atherosclerosis in WHHL Rabbit

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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.