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Thesis (M.S.)--Northern Michigan University, 2006. / Bibliography: leaves 70-72.

Thesis (Ph. D.)--University of Sydney, 2005. / Title from title screen (viewed 19 May 2008). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Heart Research Institute, Faculty of Medicine. Degree awarded 2005; thesis submitted 2004. Includes bibliographical references. Also available in print form.

published_or_final_version / Medicine / Master / Master of Philosophy

Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) is a recently identified scavenger receptor expressed in endothelial cells and mediates the uptake of oxidized LDL (oxLDL). LOX-1 expression is increased in atherosclerotic lesions in animals and humans. Recent evidence has suggested that LOX-1 is involved in the development and progression of atherosclerosis. In addition to endothelial cells, it has also been reported that LOX-1 is also expressed by other cell types like macrophages. It is a multi-ligand class E scavenger receptor and cellular expression of LOX-1 can be induced by many of its ligands. The concentration of some of these ligands like oxLDL and advanced glycation end products (AGEs) are increased in the diabetic milieu. My hypothesis is that LOX-1 expression is increased in diabetes mellitus and LOX-1 activation may play a role in the development of micro- and/or macrovascular complications of diabetes. The objective of this thesis is to elucidate the role of LOX-1 in type 2 diabetes mellitus and its complications. The effect of modified LDL and AGEs on LOX-1 expression and the cellular response upon LOX-1 activation was investigated. In vitro studies have shown that both AGEs and oxLDL can activate and increase cellular expression of LOX-1 and the soluble form of LOX-1 (sLOX-1) in cultured endothelial cells. In addition, LDL modified by glycoxidation, is also a ligand of LOX-1 and glycoxidized LDL is even more potent than oxLDL in inducing LOX-1 expression. In patients with type 2 diabetes, serum level of sLOX-1 was significantly higher than non-diabetic normal control, indicating that LOX-1 expression was increased in diabetes. Serum levels of AGEs and glycoxidized LDL were important determinants of serum sLOX-1 level, and lowering serum AGEs led to a beneficial reduction in serum sLOX-1 concentration. Hence, AGEs was clearly an important ligand of LOX-1 in diabetes mellitus, and experiments were performed to further elucidate the underlying signaling pathway involved in the up-regulation of LOX-1 by AGEs. This was mediated by ligation of AGEs to the receptor for advanced glycation end products (RAGE) and activation of phosphoinositide 3-kinase. Mammalian target of rapamycin was a found to be a key downstream intermediary in AGEs-inducible LOX-1 expression in endothelial cells. I further demonstrated that LOX-1 was also expressed in human renal mesangial cells, and expression was at a low level at basal state but inducible by its ligands. Up-regulation of LOX-1 expression in activated mesangial cells resulted in increased oxidative stress, as well as increased production of proinflammatory cytokines, chemokines and growth factors. These experimental findings would suggest that LOX-1 might potentially be involved in renal inflammation and diabetic nephropathy. The above results collectively suggest that diabetes is associated with increased LOX-1 activation, and LOX-1 may play a role in the development of diabetic complications. Hence, LOX-1 might represent a suitable target for the future development of new strategies for treating and preventing diabetic vascular complications. / published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

Studies have shown that hypercholesterolemia is a risk for cardiovascular disease; however, some normocholesterolemic individuals still develop coronary atherosclerosis. This project was undertaken to investigate the association of abnormalities of low density lipoprotein (LDL) metabolism, in the absence of hypercholesterolemia, with the development of coronary artery disease (CAD). Mononuclear leukocytes (MNL), HL-60 cells and 1,25-dihydroxyvitamin D₃-induced HL-60 macrophages were used as model systems to study the effect of an altered LDL composition on cellular lipoprotein and sterol metabolism. LDL and MNL were isolated from patients with and without CAD. The mean rate of LDL degradation was 1.7-fold higher in CAD-MNL than in control-MNL (P < 0.05), independent of the LDL source. The increased LDL degradation rate in CAD-MNL appeared to be due to an increased LDL receptor activity of CAD-MNL and not to an increased CAD-LDL interaction with the receptor since LDL isolated from patients with and without CAD had similar in vitro degradation rates by HL-60 cells and D₃-induced HL-60 macrophages. LDL from CAD patients (CAD-LDL) contained significantly less cholesteryl ester per particle than LDL from control subjects (Control-LDL). The ability of CAD-LDL and Control-LDL to regulate sterol and lipoprotein metabolism was compared in HL-60 cells. The results indicate that CAD-LDL exhibited reduced abilities to suppress receptor-mediated LDL degradation and to activate acyl-CoA:cholesterol acyltransferase as compared to Control-LDL. There was no significant difference in the rate of sterol synthesis between cells treated with CAD-LDL and Control-LDL. The data support the hypothesis that cholesteryl ester-poor CAD-LDL exhibits a decreased ability to down-regulate LDL receptor activity which could in part account for the observed increase in LDL degradation by MNL from CAD patients. A noncompetitive enzyme-linked immunosorbent assay (ELISA) was developed to measure plasma apolipoproteins (apo) A-I and B. The results indicate that a reduced plasma apo A-I level was associated with CAD patients even if there were no significant differences in the levels of high density lipoprotein cholesterol when compared with individuals without CAD.

Thesis (Ph. D.)--University of Texas at Austin, 2005. / Supervisor: Jeanne Freeland-Graves. Vita. Includes bibliographical references.

Thesis (Ph. D.)--Drexel University, 2006. / Includes abstract and vita. Includes bibliographical references.

The rates of plasma clearance of human native low density lipoproteins (LDL) and acetylated human low density lipoproteins (acetyl-LDL) were compared between copper-deficient (CuD) and copper-adequate (CuA) rats. Purified human LDL (d 1.02-1.063) were labeled with 125I and injected to fasted recipient rats intravenously. At different time intervals plasma clearance of 125I radioactivity was measured. The percent of clearance was calculated based on the total plasma volume, as determined by a radioisotopic dilution method. Native human 125I-LDL were cleared at a faster rate in CuD, compared with CuA rats. The half-times (t 1 2) of 125I-LDL clearance are 4.90 ± 0.20 and 5.80 ± 0.30 hours in CuD and CuA rats, respectively. The plasma trichloroacetic acid-soluble 125I-radioactivity was significantly and steadily increased in CuD rats at each interval, reflecting the faster clearance and degradation of LDL in those rats. The plasma removal of 125I-acetyl-LDL was faster compared with that of 125I-LDL. The half-times (t 1 2) of acetyl-LDL in CuD and CuA rats are 5.20 ± 0.06 and 5.16 ± 0.08 minutes, respectively, with no significant difference between the groups. The data indicates that the uptake of LDL via the "scavenger" receptor remains unaffected in copper-deficient rats. The faster removal of the unmodified (native) LDL in CuD group suggests that the apoB,E receptor is up-regulated in copper-deficient rats and that the hypercholesterolemia observed in copper deficiency is not associated with the defective uptake of LDL by the apoB,E-receptor dependent mechanism.

Thesis (Ph. D.)--University of Canterbury, 2006. / Typescript (photocopy). Includes bibliographical references (leaves 233-271). Also available via the World Wide Web.