Statins are 3-hydroxy, 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which block the cholesterol biosynthetic pathway to lower total serum levels and LDL-cholesterol. The cholesterol pathway also provides a supply of isoprenoids (farnesyl and geranylgeranyl) for the prenylation of signaling molecules, which include the families of Ras and Rho small GTPases. Prenyl groups provide a membrane anchor that is essential for the correct membrane localisation and function of these proteins. Statins deplete cells of lipid geranylgeranyl diphosphate (GGPP) thereby inhibiting progression of the mevalonate pathway and prenylation of proteins. Two such proteins are Rab27b and Rap1, small GTPase proteins that are involved in the secretion of platelet granule and integrin activation. We hypothesise that statins can impair prenylation of Rab27b and Rap1a in platelets and thereby attenuate platelet function. The specific aims of the project were to analyse the impact of statins on the prenylation status of Rab27b and Rap1a in platelets. As Rab27b and Rap1a are known to be involved in secretion of platelet granules a secondary aim was to analyse the downstream effects of statins on this process following activation. Finally, we assessed the impact of treatment of platelets with statins on thrombus formation, stability and resistance to fibrinolysis. Platelets incubated with statins overnight were separated into cytosolic (aqueous) and membrane (detergent) components and visualised by Western blot. An accumulation of Rab27b and Rap1a was observed in the cytosolic compartments of statins treated platelets compared to untreated platelets, thus indicating indirect evidence that statins attenuate prenylation of Rab27b and Rap1a in platelets. The most effective statin in attenuating prenylation of Rab27b and Rap1a was atorvastatin (ATV). The inhibitory effect of statins on prenylation was recovered by GGPP, indicating that the mechanism of inhibition involved the mevalonate pathway. Release of ADP from platelet dense granules was significantly impeded following overnight treatment with ATV. In line with the inhibition of prenylation of Rab27b and Rap1a by ATV, addition of GGPP rescued the release of ADP from platelet dense granules. This suggests that attenuation of dense granules release by ATV occurs via interference in the mevalonate pathway and the inhibition of Rab27b prenylation. Furthermore, ATV significantly attenuates α-granules release in thrombin stimulated platelets, which was visualised as impaired accumulation of endogenous P-selectin, PAI-1 and fibrinogen on the activated membrane. Changes in the activation of α₁₁bβ₃ integrin on the stimulated platelet surface, observed as defective binding of exogenous fibrinogen and PAC-1, were also evident following treatment of platelets with ATV. In addition, ATV treatment of platelets reduced binding of CD41a, indicating that the copy number and activation of α₁₁bβ₃ integrin on stimulated platelets was significantly reduced. Statins were also found to significantly inhibit thrombin-induced platelet aggregation following incubation of platelets overnight with therapeutic concentrations of statins. Surprisingly GGPP did not rescue platelet aggregation indicating that different mechanisms are involved in inhibition of platelet responses by statins. Incubation of whole blood with ATV overnight significantly altered several haemostatic parameters. Using thromboelastography we demonstrated a delay in the coagulation time and clot formation time. Maximum clot firmness was also significantly reduced in the presence of statins compared to the control. The effect on clot firmness generally arises from platelet dysfunction and/or a change in fibrinogen concentration and function; the latter was ruled out using a Fibtem test, which shows no difference between treated and untreated whole blood. Similarly, formation of platelet-rich plasma clots was significantly delayed following pre-treatment with ATV overnight. These clots also exhibited lower maximal absorbances, which could represent differences in the fibrin network structure. In line with the reduction in fibrinogen binding defective clot retraction was also observed in platelet-rich plasma pre-treated with ATV overnight. Similar clot retraction results were observed with tirofiban and CytoD, suggesting that the inhibitory effect of ATV may involve modulation of α₁₁bβ₃ integrin activation. Platelet-rich plasma clots formed post-treatment with statins were visualised by confocal microscopy and revealed significant alterations in clot structure; observed as thinner fibrin fibres and fewer platelet aggregates. Additionally, we demonstrated that statins modulate clot stability and shorten time to lysis. Clots formed from platelet rich plasma that was subjected to incubation with ATV overnight revealed faster lysis by tPA compared to the absence of statin. These findings are also in agreement with the lysis of Chandler model thrombi formed from overnight incubated whole blood with ATV, which demonstrated faster lysis rate mediated by tPA. Furthermore, statins were shown to change the clot thrombodynamics as assessed by HemaCore analyser, which shows that stains implicate both clot growth in response to TF-coated comb and spontaneous clot lysis by tPA. In conclusion, statins directly inhibit Rab27b and Rap1a prenylation in platelets and down-regulated dense granules release. Inhibition of Rab27b and Rap1a prenylation, and dense granules release was recovered by GGPP, indicating that these effects are mediated through the mevalonate pathway. Impairment of platelet aggregation by statins resulted via multiple mechanisms as GGPP did not recovered the inhibition of aggregation by ATV. Statins also modulate fibrinogen binding, α-granules release, clot retraction and clot formation and stability in vitro. Together these results suggest that statins may directly attenuate the platelet response in vivo. The pleotropic effect of statins on platelets may contribute to the protective function of these class of drugs in cardiovascular diseases.

Abstract not available

Background Cardiovascular disease (CVD) is the worldwide leading cause of death among non-communicable diseases and results in a huge burden of mortality and morbidity. China, a rapidly growing East Asian country, has the world largest population and is facing an increasing burden. Incidence of CVD is lower in China than in Western countries. There are more strokes, especially hemorrhagic strokes, but less coronary heart disease (CHD) in China than in Western countries. Statin, a first-choice drug for lowering low-density lipoprotein cholesterol (LDL-C), has been shown to be effective in preventing CVD and is widely used in Western countries. However, it is not known whether the same can be applied to Asian countries, where the incidence of CVD is lower and ischemic events are rarer. The aim of this systematic review is to evaluate the effectiveness of statin for prevention of CVD in East Asian populations. Methods A systematic review was conducted by searching for randomized controlled trials from 3 databases (PubMed, MEDLINE and Cochrane Trial) for prevention of CVD comparing statin with usual care or placebo in East Asian population. Data on CVD events (deaths, CHD and cerebrovascular events, rehospitalization and revascularization) and serum lipid levels (total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG)) were extracted. Risk ratios of CVD events and change in serum lipid level were tabulated. The relationship between change in serum lipid level and mortality and incidence of CVD events were also explored. Results Fourteen studies were included, with most of them (9 studies) done in Japan. Overall, statins did not significantly reduce risk of mortality, CHD events, cerebrovascular events, revascularization and rehospitalization due to CHD. However, statins consistently lowered the risk of angina-related rehospitalization by 53% (95% confidence interval (CI) 23% to 71%) and 64% (95% CI 11% to 86%) respectively in 2 studies. There was a consistent reduced risk of composite CVD events by 34% (95% CI 5% to 55%) to 54% (95% CI 6% to 41%) in 4 studies for secondary prevention. In terms of change in lipid levels, TC and LDL-C were significantly reduced by 8% to 31% and 14% to 41% respectively with statin treatment. Change in HDL-C and TG were not consistent across studies. Lowering of TC and LDL-C level was correlated with the reduction in composite CVD and CHD events. Conclusion The use of statins in East Asian populations to prevent CVD may not be as effective as in Western countries, because of the lower baseline risk and different patterns of CVD. As the prevalence of CVD risk factors increases, the incidence of CVD will increase and the pattern of CVD may change, so careful monitoring is needed. More importantly, most of the studies included had small sample sizes, short follow-up periods and/or low methodological quality, which might contribute to the inconsistent findings. A further large-scale randomized controlled trial should be done to confirm the benefits of statins among Chinese. / published_or_final_version / Public Health / Master / Master of Public Health

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Simvastatin, a commonly prescribed statin, has exhibited several unexpected non-cholesterol lowering benefits. For example, patients taking statins have a decreased mortality rate due to bactereamia, a systemic bacterial infection commonly caused by Staphylococcus aureus (S. aureus). To investigate statin protection during bactereamia, human umbilical vein endothelial cells (HUVEC) were pre-treated with simvastatin followed by infection with S. aureus, and infection was significantly decreased. Simvastatin inhibits the cholesterol biosynthesis pathway. Therefore, the protective effect of simvastatin may be due to isoprenoid inhibition, specifically, farnesyl pyrophosphate (Fpp) and geranylgeranyl pyrophosphate (GGpp). Fpp and GGpp prenylate small G-proteins that function in cytoskeletal rearrangement and endocytosis. When Fpp and GGpp were replenished, infection was not significantly reduced. Furthermore, when farnesyl transferase and geranylgeranyl transferase, enzymes essential to transfer isoprenoid group during prenylation, were inhibited a significant decrease in infection was observed. The data indicates that Fpp and GGpp are essential for S. aureus infection. / Department of Biology

Staphylococcus aureus, the most prevalant etiologic agent causing sepsis (a damaging inflammatory response), is traditionally cleared with antibiotics. Increased numbers of antibiotic-resistant strains mandate additional treatments to clear infections and prevent sepsis. There is evidence that suggests the lipid-lowering drug simvastatin may be beneficial for treating S. aureus infections due to its anti-inflammatory and immunomodulatory effects. In this study we pretreated 8-13 week old, male and female Balb/c and C57BL/6 mice with 1000 ng/g [BW] simvastatin in ethanol at 18 and 3 hours prior to S. aureus infection. We subsequently administered 10 mg/kg [BW] gentamicin in saline at 3, 6, 12, 24, and 48 hour timepoints. Another group of mice did not receive simvastatin treatment, and the final group received control treatments and was not infected with S. aureus. Our studies demonstrate that simvastatin may down-regulate sepsis-inducing inflammatory responses in S. aureus-infected C57BL/6 mice. / Department of Biology

Accompanying diskette contains data of Chapters 3, 4, 5, 7, 8 and 9 (ASCII) / Bibliography: leaves 177-207. / xiv, 208, [93] leaves : ill. ; 30 cm. + 1 computer disk (2 sided, double density ; 3 1/2 in.) / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Defines myocardial pharmacokinetic profiles using mass balance principles and correlates them with simultaneously measured myocardial pharmacodynamic profiles. / Thesis (Ph.D.)--University of Adelaide, Dept. of Anaesthesia and Intensive Care, 1992

Thesis (M.Sc.) (Honours) -- University of Western Sydney, Hawkesbury, 2001. / A thesis submitted in fulfilment of the rquirements for the award of the degree of MSc(Hons), University of Western Sydney, Hawkesbury Campus, 2001. Bibliography : leaves 263-294.

Thesis (Ph.D.)--University of Western Australia, 2006.

Thesis (Ph.D.)--University of Western Australia, 2007.