Year of Publication

2015

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Pharmacology and Nutritional Sciences

First Advisor

Dr. Alan Daugherty

Abstract

Abdominal aortic aneurysm (AAA) is a devastating disease that exhibits permanent lumen expansion typically in the infrarenal aorta. AAA is prevalent among aged population, especially in males. Despite the incidence in women is lower, studies indicate the tortuosity is more severe and aortic rupture risk is higher in women. In most patients, AAA remains asymptomatic until it ruptures leading to sudden and fatal hemorrhage.

To date, there is no proven medical therapy that can prevent the expansion or rupture. Human observational studies implicate the presence of AAA is associated with both high plasma low-density lipoprotein-cholesterol (HDL-C) and low plasma high-density lipoprotein-cholesterol (HDL-C) concentrations. To examine the role of specific lipoproteins in development of AAA, angiotensin (Ang) II-induced AAA was firstly determined in apolipoprotein AI deficient (apoAI -/-) mice in both C57BL/6 and LDL receptor deficient (LDL receptor -/-) backgrounds. The deletion of apoAI led to a significant decrease of HDL-C concentrations. However, we were unable to define any exacerbation of AngII-induced AAA in either normo- or hyperlipidemic mice with apoAI deficiency. Next we compared AngII-induced AAA formation using multiple mouse strains with dietary manipulation to generate different severities of hypercholesterolemia. We demonstrated the apolipoprotein B (apoB)-containing lipoproteins promoted the development of AngII-induced AAA. Moreover, ezetimibe administration significantly reduced both apoB-containing lipoproteins and AAA formation. Together, our studies demonstrate that elevated apoB-containing lipoproteins, contribute to the development of AngII-induced AAA.

To investigate the role of apoB-containing lipoproteins on established AAA, male LDL receptors -/- mice fed a Western diet were infused with AngII for 4 weeks to induced AAA. Then mice with AAA were stratified into either a group maintained on western diet or switched to a normal diet. AngII infusion was continued for an additional 8 weeks. The diet switch resulted in significantly reduced plasma cholesterol concentrations, which was attributable to the decrease of apoB-containing lipoproteins. We found a profound inhibition of aneurysm progression in diet switched mice associated with attenuated macrophage accumulation and medial thickening. Collectively, our data demonstrate that apoB-containing lipoproteins promote the progression of established AAA.

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