The proposed research will examine the influence of social environment on hyperlipidemic, oxidative, andinflammatory mechanisms of atherosclerosis in the Watanabe Heritable Hyperlipidemic rabbit (WHHL).Previous research from our laboratory demonstrated that WHHLs allowed to maintain stable relationships, asopposed to WHHLs housed alone or subjected to unstable relationships, showed a significant decrease inthe progression of atherosclerosis. An unstable social environment, characterized by agonistic behavior andemotional stress, was associated with the development of severe atherosclerotic lesions (fibrous caps,necrosis, calcification), whereas individually-caged WHHLs developed extensive lesions that were not asadvanced (primarily foam cells and fatty streaks). The individually-caged WHHLs were also behaviorallysedentary, 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 ina predominantly genetic model of disease. Based on preliminary data, it is hypothesized that socialenvironment differentially modulates inflammatory and oxidative stress mechanisms responsible for diseaseprogression. Hyperlipidemia, which is common to all WHHLs, is viewed as a primary risk factor capable ofdirectly stimulating the formation of vascular foam cells and fatty streaks. Over time, oxidative stress andinflammatory mechanisms are activated, which accelerates progression of disease, leading to moreadvanced lesions and vulnerable plaque. It is proposed that atherosclerosis in the Stable Social Groupprogresses 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 behavioralinactivity and hyperinsulinemia leads to rapid development of foamy, fatty lesions in vulnerable regions of theaorta. We hypothesize that the Unstable Social Group develops lesions of similar size and location to theIndividually-Caged animals due to the hyperlipidemic mechanisms, however, disease severity progressesmore 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, thespecific aims of the project are: 1.) To assess the influence of plasma oxytocin, as a function of socialenvironment, on vascular oxidative stress, inflammation, and atherosclerosis in the WHHL model, 2.) Tomeasure the effects of NAD(P)H oxidase antagonism, or angiotensin receptor (AT1) antagonism, on theprogression of atherosclerosis as a function of social environment, and 3.) To assess the role ofproinflammatory cytokines and CRP on disease progression as a function of social environment, and theeffects of SNS antagonism on these inflammatory mechanisms.
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