Date of Award

2017

Document Type

Open Access Dissertation

Department

Biomedical Science

Sub-Department

School of Medicine

First Advisor

Daping Fan

Abstract

Atherosclerosis is both a chronic inflammatory disease and lipid deposition disorder characterized by accumulation of lipids, fibrous tissue, and inflammatory cells in the arterial wall. Thus, investigating the role of inflammation and the immune system in the progression of atherosclerosis may help in the development of novel therapeutics for atherosclerotic disease. Current atherosclerosis therapy is aimed at lipid targets and focused primarily on reducing plasma cholesterol levels. Clinical and experimental data support the critical role of inflammation in atherosclerosis and suggest that reducing inflammation even without affecting lipid levels may reduce the event rate of cardiovascular disease. Yet, no pure antiinflammatory drugs are used to treat patients with atherosclerotic diseases. Recently, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) provided evidence that targeting inflammation by inhibiting IL1-β reduced the rate of cardiovascular events, providing support for the inflammation hypothesis of atherosclerosis. In this study, we aim to test the inflammation hypothesis using various immunomodulatory approaches. First, we measured the expression of inflammation markers in human atherosclerotic carotid arteries. We demonstrated that markers of inflammation were significantly increased in plaques compared to normal media and those markers positively correlate with miR155, a pro-inflammatory microRNA. We observed that miR155 was up-regulated in the calcified media occurred concomitant with osteogenic genes; and cell culture and mouse studies further suggested a causal role of miR155 in vascular calcification. In the second study we observed that bone marrow tristetraprolin (TTP) deficiency in LDLR-/- mice significantly increased systemic inflammation. Unexpectedly, serum lipid levels and hepatic steatosis were dramatically reduced, likely due to reduced lipid production in the liver by downregulating SREBF1. Increased inflammation and reduced serum lipid offset each other and result in unchanged atherosclerosis. This model may provide an opportunity to examine the relationship between inflammation and lipoprotein metabolism. We also investigated the effect of macrophage-specific GP96 deficiency on atherosclerosis to determine the role of toll like receptors (TLRs) during atherogenesis. Our results show that macrophage-specific GP96 deficiency did not change inflammatory status, serum lipid, and atherosclerosis in LDLR-/- mice. Sparstolonin (SsnB), a selective TLR2/TLR4 inhibitor, is known to have anti-inflammatory effects. In this study, we injected mice with super-low dose LPS or LPS plus SsnB. Super-low dose LPS increased serum chemo-attractants, while SsnB reduced these chemokines. However, super-low dose LPS and SsnB administration did not affect atherosclerotic lesions. Atherosclerosis is a complex, multifactorial process, and the interaction between inflammation and atherogenesis is complicated as indicated by our results. Since CANTOS shows that targeting inflammation reduced the rate of cardiovascular events, it opens the field to further examine the inflammation hypothesis of atherosclerosis and to explore novel therapeutic avenues by targeting inflammation

Rights

© 2017, Fatma Saaoud

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