Nkambule, Bongani Brian.Fabunmi, Oyesanmi Abisoye.2024-12-052024-12-0520232023https://hdl.handle.net/10413/23453Doctoral Degree. University of KwaZulu-Natal, Durban.Introduction Obesity is a prominent feature of metabolic syndrome that can predispose an individual to an increased risk of developing type 2 diabetes (T2D) and cardiovascular disease (CVD). Moreso, oral contraceptives are associated with an increased risk of cardiovascular-related complications such as arterial and venous thrombosis in some women of reproductive age. There is a need to understand how the usage of combined oral contraceptives (COC) affectswomen with diverse metabolic complications. Thus, we aimed to evaluate CVD-related risk factors, especially those implicating atherothrombosis, in a preclinical model of high-fat diet (HFD) exposure to COC. We also assessed whether switching to a low-fat diet or pharmacologic intervention with low-dose aspirin (LDA) could improve the metabolic status or alleviate CVD risk using this preclinical model of HFD. Methods The study was divided into three phases to achieve its aims. The study's first phase was used to establish a preclinical model of impaired glucose tolerance and to test the efficacy of COC. Thus, female Sprague Dawley rats were randomly assigned to receive HFD and low-fat diet (LFD) for eight weeks before assessing basic metabolic parameters or CVD-related abnormalities. The study's second phase involved testing the detrimental effects of COC, where rats switched from HFD to LFD for an additional six weeks while receiving either a high (HCOC) or low dose (LCOC) of COC. The third phase of the study involved rats exposed to COC for six weeks before treatment with LDA for another four weeks. At the end of each experimental phase, measurements for basic metabolic status and CVD-related parameters were taken. These included the animal body weights, insulin levels, lipid profiles, fasting blood glucose, hematological indices, blood pressure and heart rate, as well asmarkers of immune activation such as interleukin (IL)-6, tumor necrosis factor-alpha (TNF)-α, factor (TF) and D-dimer, Von Willebrand factor (vWF) and nitric oxide. Results The results of the first phase indicated that exposure to HFD led to a marked weight gain, impaired glucose tolerance, and abnormal lipid profiles, including obscured triglycerideglucose index when compared to rats in the LFD group (p < 0.001). Rats exposed to HFD also presented with increased markers of CVD risk, accompanied by a pro-inflammatorystate, as displayed by increased levels of IL-6 and TNF-α compared to the LFD group (p <0.05). Interestingly, dietary intervention and switching from an HFD to an LFD could improve metabolic status and potentially lower CVD-risk-related markers. However, this improvement was not seen in rats that received HCOC, as these animals impaired metabolic state that was accompanied by alteration in the levels of immune activation, coagulation, and endothelial function. However, the third phase of the study showed that short-term LDA treatment for four weeks could improve the metabolic status and decrease the markers of immune activation (IL-6, TNF-α, and MCP-1) in animals that received HCOC. LDA also decreased the bleeding time and makers of hypercoagulation (TFand dimer), as well as improved endothelial function by increasing the availability of nitric oxide and decreasing levels of vWF in rats that were exposed to HCOC treatment (p < 0.05). Conclusion Our results indicated that exposure to HFD was consistent with impaired glucose tolerance and increased CVD risk in female rats. Exposure to HCOC was associated with an increased risk of atherothrombotic disorder in HFD animals despite dietary intervention that involved switching from an HFD to an LFD. Short-term LDA attenuates the risk of atherothrombotic disorder by improving the metabolic status and decreasing markers of immune activation, hypercoagulation, and endothelial dysfunction during exposure to COC treatment in animals. Our result demonstrated that an increased risk of thrombotic events during COC treatment may potentially be associated with the dose and duration of treatment. While the use of LDA may be of potential therapeutic benefit against the risk of atherothrombotic disorder following toxic exposure to COC. However, further studies are needed to confirm the interaction mechanism between the several types of available COC, further revealing the potential therapeutic value of LDA.enLow-dose aspirin.Thesis