Abstract The cholesteryl ester transfer protein (CETP) is a plasma protein that transfers cholesteryl esters and triglycerides between plasma lipoproteins. Humans with a genetic CETP deficiency have high plasma high density lipopoprotein cholesterol (HDL-C) levels, whereas the CETP transgene lowers plasma HDL-C levels in mice. The role of CETP in the development of atherosclerosis is unclear due to the controversial results of many human and animal studies. The present research was designed to investigate the CETP gene as a candidate gene in the regulation of plasma HDL-C levels and the development of atherosclerosis in humans. The CETP gene was screened for mutations and polymorphisms associated with these traits in a well-characterized, homogenous population sample of 515 men and women and in a sample of 115 men with low HDL-C levels and coronary heart disease (CHD). Using polymerase chain reaction and single-strand conformation polymorphism analysis (PCR-SSCP), three polymorphic sites were found (A373P, I405V, R451Q) in the exons of the CETP gene, one in intron 9 and one in the 3'untranslated region of the CETP gene. In addition, the genotypes of a functional promoter polymorphism were determined. The V405 allele was associated with lower plasma CETP activity in the whole population sample, and the Q451 allele and the P373 allele were associated with higher plasma CETP activity in men, whereas the genotypes of the promoter polymorphism were not significantly associated with plasma CETP activity. The genotypes of the CETP gene explained about 20 % of the variation of plasma CETP activity in men. The CETP gene polymorphisms were found to be a minor regulator of plasma HDL-C levels, and these associations interacted with alcohol consumption, sex and triglyceride levels. The strongest association was detected between the promoter polymorphism and HDL-C levels in women. The variation at the CETP gene locus explained about 8 % of the variation in plasma HDL-C levels in women, but less than 1 % in men. CETP gene polymorphisms (A373P, I405V and R451Q) were associated with carotid intima-media thickness, explaining about 6 % of the variation in men and 4 % in women. However, none of the polymorphisms were associated significantly with the CHD risk. In conclusion, the CETP gene was found to be polymorphic and a minor regulator of plasma HDL-C levels and the development of atherosclerosis.

Magister Pharmaceuticae - MPharm / Cardiovascular diseases (CVDs) such as ischaemic heart diseases, heart failure and stroke remain a major cause of death globally. Various deep-rooted factors influence CVD development; these include but are not limited to elevated blood lipids, high blood pressure, obesity and diabetes. A considerable number of proteins are involved directly and indirectly in the transport, maintenance and elimination of plasma lipids, including high and low-density lipoprotein cholesterol (HDL-C and LDL-C). There are several mechanisms involved in the removal of LDL particles from systemic circulation. One such mechanism is associated with the gene that encodes proprotein convertase subtilisin/kexin type 9 (PCSK9), which has become an exciting therapeutic target for the reduction of residual risk of CVDs. Currently, statins are the mainstay treatment to reduce LDL-C, and a need exists to further develop more effective LDL-C-lowering drugs that might supplement statins. This study was aimed at contributing to the generation of knowledge regarding the effect of niacin in reducing LDL levels through PCSK9 interaction.

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Prior studies of lipid and lipoprotein levels alterations associated with the administration of danazol, a testosterone derivative, in patients treated for endometriosis have been conflicting. We administered danazol to 7 normal menstruating women and measured plasma lipid and lipoprotein cholesterol levels prior to and 2 months after treatment. Small, non-significant decreases in total plasma cholesterol and triglyceride levels were seen, largely due to a dramatic decline in one woman with type IV hyperlipoproteinemia. No significant change in low density or very low density lipoprotein cholesterol levels was seen. However, a marked (40%) reduction of high density lipoprotein cholesterol level in the mean was found. These findings have implications for the atherogenic potential of danazol, the treatment of hyperlipidemia, and the relationship between gonadal hormones and lipoprotein levels.

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The occurrence of deformation in plastic bottles is a common problem in the bottling industry where bottles are blow molded, hot filled at high temperatures and sealed. Plastics have unique properties that make it difficult to predict when and why such changes may occur. The root cause of such deformation is unknown by many bottle producers and recent attempts have been made to minimize the occurrence of such defects. The purpose of this research is to determine which variables involved in the bottle production process influence bottle shape. Earlier variables that were tested included both blow molding resin and total bottle sidewall thickness. The result of changing these variables did not create a decrease in defects. The use of an Ishikawa fishbone diagram identified hot filling temperature a major variable that influences final bottle shape. This research summarizes the results of a series of tests that were developed to observe the effect of hot filling temperature on final bottle shape. A positive correlation between sidewall deflection and liquid hot filling temperature was observed. A series of tensile tests were also developed to analyze the strength of various regions of a blow molded bottle. An early Pareto Analysis determined that the parting line is more susceptible to defects than any other region of the bottle. This weakness was confirmed after the tensile tests proved that there is a statistically significant difference between measurements on the sidewall and parting line (pvalue < .001). The results of this thesis highlight the consequences of arbitrarily choosing a filling temperature with little understanding of the bottle's strength at high temperatures. Plastic bottle producers and hot filling companies should unite to determine the appropriate hot filling temperature before bottles are molded and filled.

Atherosclerosis is a chronic inflammatory disease affecting large- and medium-sized arteries and is considered the major cause behind cardiovascular diseases (CVD). Elevated low-density lipoprotein (LDL)-cholesterol and low high-density lipoprotein (HDL)-cholesterol are considered major risk factors for the CVD. HDL mediates a variety of atheroprotective actions, many of them involving the interaction with the scavenger receptor class B, type 1 (SR-B1). Despite the efforts placed in raising HDL-cholesterol, no improvement has been achieved in reducing CVD risk, suggesting that other components of the HDL particles may be responsible for HDL-mediated atheroprotection. One of these may be sphingosine-1-phospate (S1P). In this thesis, the role of S1P receptors (S1PRs) in atherosclerosis is explored, with emphasis in macrophage apoptosis. In particular, the importance of the macrophage S1PR1 and its role in apoptosis and atherosclerosis was evaluated. We demonstrated that diabetes exacerbates atherosclerosis development and myocardial infarction in SR-B1 KO/apoE-hypomorphic mice and that treatment with FTY720, a S1PR agonist, protects against diabetes pro-atherogenic effects. We also show that S1PR1 agonists protected macrophages against apoptosis through phosphoinositide 3-kinase (PI3K)/AKT, and that HDL failed to protect S1PR1 deficient macrophages against apoptosis. In vivo, macrophage S1PR1 deficiency translated into increased atherosclerosis, necrotic core formation and numbers of apoptotic cells in the atherosclerotic plaque. BIM deficiency in BM cells was protective against atherosclerosis development and HDL treatment reduced BIM protein levels in cells exposed to ER stressors, suggesting that the pro-apoptotic protein may be an important target for HDL in macrophages. We conclude that signaling through the S1PRs, in particular S1PR1 is important in controlling macrophage apoptosis and atherosclerosis development. Our data suggests that S1PR1 signaling axis and the pro-apoptotic protein BIM play an important role in mediating HDL anti-apoptotic signaling, however further studies are required to clarify the interaction between all of these factors. / Thesis / Doctor of Philosophy (PhD)

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