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(2022) Bello, IdrisThesisThe inflammatory artery diseases atherosclerosis and abdominal aortic aneurysm (AAA) are major causes of morbidity and mortality and there is significant attention towards identifying and targeting prominent inflammatory mediators underpinning these cardiovascular diseases. In the first chapter, the role of the pro-inflammatory and pro-oxidant enzyme myeloperoxidase (MPO) in inflammatory artery disease was studied. A clinical study showed that while circulating plasma MPO levels were not different in AAA patients versus healthy controls, immunohistochemistry showed that the MPO protein was prevalent in human AAA tissue. In the angiotensin II (AngII)-infusion model of AAA and atherosclerosis in apolipoprotein-E gene-deficient (ApoE–/–) mice, administration of 2-thioxanthines (2-TX), a clinically-trialled MPO inhibitor, significantly inhibited AAA but not atherosclerosis. Paradoxically, MPO gene-deficiency did not affect AngII-induced AAA but attenuated atherosclerosis. Notably, 2-TX significantly inhibited AAA in ApoE–/–MPO–/– mice, indicating 2-TX protects against aortic disease in the absence of MPO. The role of MPO in the diabetes-accelerated atherosclerosis in ApoE–/– mice was also examined. While MPO gene-deficiency did not impact on the degree of diabetes it significantly reduced diabetes-accelerated atherosclerosis at the brachiocephalic artery and aortic sinus, but not aortic arch, indicating that MPO exhibits site-specific effect on atherosclerosis. A second chapter focused on semicarbizide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1), a pro-inflammatory enzyme that facilitates the vascular recruitment of activated leukocytes. Treatment of AngII-infused ApoE–/– mice with a clinically-viable SSAO/VAP-1 inhibitor significantly protected against AAA and atherosclerosis, independent of alterations to plasma lipid levels. A third chapter tested the therapeutic efficacy of apolipoprotein A-I (ApoA-I), the major cardioprotective protein in high-density lipoproteins, and a class of immunomodulatory nanoparticles (INPs), which selectively target and disable a pro-inflammatory monocyte subset. Although ApoA-I treatment did not impact on the development of arterial disease in AngII-infused, aged ApoE–/– mice, INPs provided significant protection against AAA and atherosclerosis in these mice. This novel research provides new insights on the roles of MPO and SSAO in AAA and atherosclerosis and identified clinically-viable inhibitors of MPO and SSAO and a class of biodegradable immunomodulatory nanoparticles as potential new therapeutics for treating inflammatory artery disease.
(2023) Luque, NathanThesisIntroduction: Preeclampsia (PE) causes significant maternal and foetal morbidity and mortality. The causes of PE remain unknown, but uterine or placental vascular endothelial dysfunction/damage are thought to contribute to the pathology of this condition. The potential use pravastatin for the treatment of PE has been reported by multiple studies, however the mechanism(s) behind this is have yet to be elucidated. Aims: To investigate the effect of pravastatin on uterine microvascular endothelial function and caveolae form and distribution in PE Methods: Myometrial radial arterioles from caesarean-section normotensive (NT) and PE patients were incubated with pravastatin (2mM/6h) in vitro. Electron microscopy, immunofluorescence, qPCR and pressure myography were used to characterize caveolae, microdomain signalling, and vessel structure and function. Parallel studies with methyl-β-cyclodextrin (MβCD) (10mM/1h) examined the direct effects of removing membrane cholesterol on vascular function and anatomy. Results: Endothelium-dependent relaxation induced by bradykinin (ByK) was diminished in PE vs NT, associated with loss of nitric oxide (NO) and BKCa mediated dilation, PE vasodilation being SKCa mediated; PE vessels retained vasodilatory response to NO donation. Pravastatin incubation restored PE dilatory function to NT levels by enhancing NO, IKCa and BKCa-mediated components of relaxation; PE vessels exhibited increased stiffness vs NT associated with increased vessel wall cross sectional area; Pravastatin incubation did not affect vessel stiffness in PE or NT; MβCD increased vessel stiffness in NT, whilst PE vessels displayed no change. MEGJ and caveolae/vesicle density was lower in PE than NT; Pravastatin incubation significantly increased MEGJ and lumenal caveolae/vesicle density in PE, while significantly decreasing caveolae and vesicle density throughout NT endothelium; MβCD increased ablumenal caveolae/vesicle density in PE, and produced qualitative reductions in caveolae/vesicles in NT. Cav-1 and IKCa protein expression was decreased in PE vs NT, Cav-1 increased by pravastatin incubation in PE. CAV3 mRNA expression was increased in PE vs NT, but not CAV1, CAV2, CAVIN1 or CAVIN2. Discussion: This thesis reports restored PE dilation to Byk to NT with pravastatin, through mechanisms and structural alterations which are beneficial yet differ considerably from NT, reflecting the altered organisation and regulation of myometrial arteries in this disease state.