Atherosclerotic Plaque Stability and Vascular Repair
Abstract: Myocardial infarction and stroke are two of the most common causes of death in the world, mainly caused by a rupture of an atherosclerotic plaque. A vulnerable atherosclerotic plaque is a high-risk plaque that can form a thrombus by rupture. The phenotype of a plaque prone to rupture includes a thin fibrous cap, a large lipid core, accumulation of macrophages, a fissured fibrous cap and high-grade stenosis. The aim of this thesis has been to investigate plaque vulnerability and vascular repair processes. We studied androgen-deprivation therapy for prostate cancer and its effects on plaque vulnerability in a mouse model of atherosclerosis where we alter shear stress to induce plaques with advanced or fibrous phenotypes. Androgen-deprivation therapy has been associated with increased risk for development of cardiovascular events and recent pooled analyses suggest that this primarily is the case for patients with pre-existing cardiovascular disease treated with gonadotropin-releasing hormone receptor agonists. In the present study, the gonadotropin-releasing hormone receptor agonists caused necrosis-like areas in fibrous plaques from ApoE deficient mice after 4 weeks of treatment. This suggests that there are direct drug related interactions with the atherosclerotic plaque. The effects of androgen-deprivation therapy on cardiovascular disease need to be further studied. In the same mouse model just mentioned, we studied IL-22 deficiency in vascular tissue repair. IL-22 attenuates plaque development in advanced plaques, but not in fibrous lesions, and appears to ease the differentiation of SMC that promotes early plaque growth. The specific role that IL-22 plays in atherosclerosis is yet to be determined. We do know that IL-22 has been found in abundance in carotid plaques from symptomatic patients. Patients with acute myocardial infarction have also been found with a remarkable rise in IL-22 plasma levels, compared with patients with controls. Diabetes is a riskfactor for cardiovascular disease. To investigate vascular repair mechanism in hyperglycemia per se, without the involvement of dyslipidemia and subsequent inflammation, we induced carotid neointimal hyperplasia in the Akita mouse. We found that hyperglycemia does not alter vascular repair in our mouse model of neointimal hyperplasiaAfter having to discard a study using diabetic OPN deficient mice, we have isolated and tested OPN deficient beta cells to gain a better understanding of the role of OPN in beta cell function. Our study showed that OPN deficiency in the mouse pancreatic beta cells results in negative alterations of beta-cell physiology that appear to be compensated for in a healthy physiological state. In the OPN-/- mouse we detected three important alterations in the beta cells: elevated Ca2+ levels, morphological modifications of the endoplasmic reticulum and altered insulin vesicle localization. These findings indicate that reduced levels of OPN could in the long run be a factor contributing to development of beta cell failure.
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