Statins are widely used to treat hypercholesterolemia. Statins inhibit cholesterol biosynthesis, thereby activating genes involved in cholesterol homeostasis, which are under the control of the Sterol Regulatory Element (SRE). Statins also have cholesterol-independent beneficial cardiovascular effects mediated through the phosphoinositide 3-kinase (PI3-K) / Akt signaling pathway and by inhibition of protein prenylation. Because statins inhibit the synthesis of isoprenoids, they can act by inhibiting the small signaling GTPases Ras and Rho, which require post-translational prenylation to become membrane-anchored and functional. We showed that simvastatin-mediated inhibition of protein prenylation does not appear to play a role in activation of SRE transcriptional activity in HepG2 cells. We also found that when isoprenoids were replenished, basal phospho-Akt decreased, suggesting that inhibition of prenylation by simvastatin mediates Akt phosphorylation. Future studies will be needed to investigate the role that inhibition of protein prenylation plays in the activation of the PI3-K/Akt pathway by simvastatin. / Department of Biology

Staphylococcus aureus is a common and versatile opportunistic pathogen in humans. Increases in the incidence of community acquired and nosocomial infections, coupled with the emergence of antibiotic resistant strains, are causing new treatment challenges for health care professionals. S. aureus readily binds to the endothelial cell surface and utilizes host cell endocytosis to evade host cell immune responses. Inhibition of endocytosis may cause S. aureus to remain unprotected at the host cell surface, allowing host immune systems and other therapeutics more time to clear an infection. Simvastatin inhibits host cell endocytosis. We hypothesize that using simvastatin to inhibit S. aureus invasion of host cells, a high throughput, small molecule screen can be developed. The high throughput screen will evaluate the National Institutes of Health small molecule library for compounds that better inhibit endocytosis. Additionally, 2-dimensional gel electrophoresis will be performed to elucidate the pathway simvastatin alters to inhibit endocytosis. / Department of Biology

Sepsis is a systemic inflammatory response that causes, increased heart rate, respirations, fever, and inadequate blood flow to organs. One of the most prevalent causes of sepsis is Staphylococcus aureus (S. aureus). With increasing numbers of strains of bacteria becoming antibiotic resistant, new methods for the treatment and clearance of sepsis are needed. Studies have shown that the lipid lowering drug simvastatin is protective for incidence of sepsis, having immunomodulatory effects and anti-inflammatory properties, specifically. Thus, it may be an alternative way to prevent sepsis due to S. aureus infections. Studies in our laboratory have shown that simvastatin pretreatment increases survival of mice infected with S. aureus and alters the adaptive immune response such that levels of IgG2c are reduced to the level of uninfected controls. Our studies have demonstrated that while simvastatin does not enhance bacterial clearance, or affect serum C5a levels, it does decrease serum levels of TNF. / Department of Biology

Access to abstract restricted until May 2016. / Access to thesis restricted until May 2016 / Department of Biology

This thesis discussed the cardiovascular effects of the aqueous leaf extract and a fraction of the methanol extract of Leonotis leonurus, a plant commonly used in traditional medicine in South Africa for the treatment of hypertension and other cardiac problems. The cardiovascular effects was tested on anaesthetized normotensive male Wistar rats and isolated perfused rat hearts.

[Truncated abstract] The metabolic syndrome is characterized by cardiovascular risk factors including dyslipidemia, insulin resistance, visceral obesity, hypertension and diabetes. The dyslipidemia of the metabolic syndrome includes elevated plasma triglyceride and apolipoprotein (apo) B levels, accumulation of small, dense low-density lipoprotein (LDL) particles and low high-density lipoprotein (HDL) cholesterol concentration. However, the precise mechanisms for this dyslipoproteinemia, specifically low plasma HDL cholesterol, are not well understood. This thesis therefore, focuses on HDL, its structure, function and metabolism. However, lipoprotein metabolism is a complex interconnected system, which includes forward and reverse cholesterol transport pathways. Hence, this thesis also examines and discusses the metabolism of apoB-containing lipoproteins. This thesis tests the general hypothesis that apolipoprotein kinetics are altered in the metabolic syndrome, and that lipid regulating therapies can improve these kinetic abnormalities. The aims were first, to compare and establish the clinical, metabolic and kinetic differences between metabolic syndrome and lean subjects; and second, to determine the regulatory effects of statin therapy, specifically, rosuvastatin on lipoprotein transport in the metabolic syndrome. Five observation statements were derived from the general hypothesis and examined in the studies described below. The findings are presented separately as a series of original publications. Study 1 Twelve men with the metabolic syndrome and ten lean men were studied in a case-control setting. ... These findings explain the HDL raising effects of rosuvastatin in the metabolic syndrome. Collectively, these studies suggest that the dyslipidemia of the metabolic syndrome results from increased production rates of VLDL and LDL particles, reduced fractional catabolic rates of these lipoproteins, together with accelerated catabolism of HDL particles. Treatment with rosuvastatin increases the catabolic rates of all apoB-containing lipoproteins and at a higher dose, decreases LDL apoB production. These effects are consistent with inhibition of cholesterol synthesis leading to an upregulation of LDL receptors. Rosuvastatin decreases the fractional catabolism of HDL particles. The effects of rosuvastatin on HDL kinetics may be related to a reduction in triglyceride concentration and cholesterol ester transfer protein activity. These findings are consistent with the general hypothesis that apolipoprotein kinetics are altered in the metabolic syndrome, and that statin therapy improves these kinetic abnormalities.

Thesis (Ph. D.)--University of Texas at Austin, 2008. / Vita. Includes bibliographical references.

Thesis (Ph. D.)--University of Hong Kong, 2008. / Includes bibliographical references (leaves 156-176) Also available in print.

Thesis (Ph. D.)--University of Hong Kong, 2008. / Includes bibliographical references (leaves 156-176) Also available online.

Thesis (Ph. D.)--Oregon State University, 2010. / Printout. Includes bibliographical references (leaves 132-147). Also available on the World Wide Web.