All ETDs from UAB

Advisory Committee Chair

Rakesh P Patel

Advisory Committee Members

C Roger White

Janusz Kabarowski

Scott Barnum

Silvio H Litovsky

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Atherosclerosis is a chronic inflammatory disease of the vessel wall and underlying cause of most cardiovascular disease. Much is understood about the nature of atherosclerosis development, including contributions from leukocytes that drive the disease process forward. The general process by which leukocytes are trafficked to sites of atherosclerosis development, and sites of inflammation in general, is understood and relies upon endothelial expressed protein adhesion molecules which serve as ligands for cognate leukocyte receptors. While these adhesion molecules share the post-translation modification of N-glycosylation, relatively little is known as to what functional role these modification plays in: i) interactions of leukocytes with inflamed endothelial cells and ii) the function(s) of individual adhesion molecule proteins. Data herein will show that upon both chemical and mechanical stimulation endothelial cells express increased levels of high mannose and hybrid N-glycans. Further studies reveal these N-glycans are also enriched in early atherosclerotic lesions in both mice and humans. The mannose residues on these glycans are shown to regulated monocyte adhesion in the presence of flow but not under static conditions. The Intracellular Adhesion Molecule-1 (ICAM-1) is identified as a scaffold for these high mannose N-glycans in both cultured endothelial cells and human coronary arteries. Finally, data demonstrate that all ICAM-1 glycoforms can mediate monocyte adhesion, but that HM-ICAM-1 displays reduced interactions with the actin cytoskeleton.

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