Abstract 1104: Investigation Into The Potential Role Of Perceived Loneliness And Endothelial Dysfunction In A Community-based African American Cohort At-risk For Cardiovascular Disease: A Translational Approach

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Background: Chronic stress is a significant contributor for cardiovascular disease (CVD) and existing health disparities. Loss of endothelial barrier integrity is a hallmark of CVD, but little is known how chronic stress impacts endothelial barrier integrity. This study aimed to investigate the signaling pathways of how loneliness-related chronic stress could impact endothelial barrier integrity. Methods: We examined the relationship among validated questionnaires of loneliness-related chronic stress and various hormonal and cytokines in a community-based cohort of African American adults at risk for CVD from resource-limited neighborhoods . Then, we conducted ex vivo as well as in vitro experiments to probe these effects and investigate the mechanism of action. Results: We determined that a 1-SD increase in loneliness was associated with a 0.32-increase (p=0.04) in the product of epinephrine (E, a catecholamine increased in individuals experiencing chronic stress) and TNFa (T, a cytokine increased in individuals experiencing loneliness), suggesting a synergism between epinephrine and TNFa. In ex vivo experiments, the product of E*T was associated with a loss in endothelial VE-cadherin expression (p=.03). In subsequent in vitro experiments to investigate this effect we treated human aortic endothelial cells with E, T, or their combination; together, these biomarkers decreased endothelial VE-cadherin expression (E: 0.94 ± 0.11, T: 0.79 ± 0.05 vs E+T: 0.58 ± 0.06-fold change of control, p<0.01) and dampened endothelial barrier integrity by increasing inter-endothelial gap formation (E: 1.59 ± 0.16 and T: 1.65 ± 0.17 vs E+T: 2.25 ± 0.13-fold change of control, p<0.001). Furthermore, we determined that the impact of E+T on endothelial cells is JAK/Stat signaling pathway dependent, establishing a putative mechanism. Conclusions: We found that a combination of epinephrine and TNFa decreased endothelial barrier integrity, suggesting an additive effect potentially accelerating CVD development and progression in individuals experiencing loneliness-related chronic stress. We provide a potential mechanism by which chronic stress could impact endothelial barrier integrity and function - ultimately worsening CVD health disparities.

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