Publication Date

2009-06-25

Availability

Open access

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Psychology (Arts and Sciences)

Date of Defense

2009-01-12

First Committee Member

Philip M. McCabe - Committee Chair

Second Committee Member

Neil Schneiderman - Committee Co-Chair

Third Committee Member

Edward Green - Committee Member

Fourth Committee Member

Julia Zaias - Committee Member

Fifth Committee Member

Armando Mendez - Committee Member

Abstract

Background. Social deprivation or isolation accelerates the progression of atherosclerosis in several animal models of the disease. Conversely, stable social environment has been associated with reduction in the extent and severity of atherosclerosis. While positive social interactions are thought to be related to this protective effect, little is known about the physiological mechanisms responsible. Recently, the neurohypophyseal peptide, oxytocin (OT), has been found to play a role in both positive social interactions and cardiovascular homeostasis, suggesting that this neuropeptide may be responsible for mediating the beneficial effects of positive social environment on atherosclerosis. The first aim of the current study is to examine the potential anti-inflammatory effects of OT on in vitro cellular models involved in the pathophysiology of atherosclerosis. The second aim is to examine whether long-term administration of OT slows the progression of atherosclerosis in apoE-/- mice. The third aim is to obtain evidence in vivo that OT is impacting disease through novel anti-inflammatory effects on tissues important in atherogenesis. Methods. 1) Human macrophage-like (DTHP-1) cells and human aortic endothelial cells (HAECs) were stimulated with lipopolysaccharde (LPS) alone, and in the presence of different concentrations of OT, and IL-6 secretion was measured. 2) ApoE-/- mice were socially isolated at 12 weeks of age and continuously infused with OT (n=24) or vehicle (n=21) from subcutaneously implanted osmotic minipumps for 12 weeks. Plasma levels of lipids, adiponectin, insulin, and CRP were assessed pre- and post-treatment. Extent of aortic atherosclerosis (percent lesion area) was assessed post-treatment and areas of high lesion prevalence were compared between OT and vehicle (VH) control groups. Constitutive release of IL-6 from ex vivo adipose tissue samples taken from a subset (n=12/group) was compared between treatment groups. Results. 1) OT demonstrated dose-dependent inhibition of LPS-induced IL-6 secretion from macrophages (35-55%, p < 0.01) and aortic endothelial cells (15-25%, p < 0.01). 2) ApoE-/- mice continuously infused with OT displayed decreased plasma CRP levels after 6 weeks of treatment and diminished lesion area at the thoracic aorta after 12 weeks of treatment relative to vehicle control animals (37%, p < 0.05). Additionally, adipose tissue samples taken from OT infused mice showed decreased constitutive release of IL-6 (30%, p < 0.01). These findings were unrelated to changes in plasma lipids, insulin, physical activity levels, or 24-hour corticosterone secretion. Discussion and Conclusions. These findings demonstrate that OT is capable of inhibiting stimulated pro-inflammatory cytokine production in macrophages and aortic endothelial cells in vitro, and constitutive release from adipose tissue in vivo. OT also decreased circulating CRP levels and slowed the progression of early stage atherosclerosis in an aortic region of high lesion prevalence in socially isolated apoE-/- mice. Taken together, these results suggest that increased peripheral OT could be partially responsible for the beneficial effect of positive social environment on atherosclerosis.

Keywords

Oxytocin; Atherosclerosis; Social Isolation

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