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Atherosclerosis is a major underlying cause of cardiovascular disease; however, the molecular mechanisms by which cardiovascular risk factors promote the development of atherosclerosis are poorly understood. Recent evidence from our laboratory suggests that endoplasmic reticulum (ER) stress signaling through glycogen synthase kinase (GSK)-3α/β is involved in the activation of pro-atherosclerotic processes. Previous studies from our lab show that myeloid-specific deletion of GSK3α attenuates the progression of atherosclerosis. However, the precise role(s) of GSK3α/β in atherosclerotic regression is not known. The primary goal of this thesis is to investigate the role(s) of GSK3α/β in lesional macrophages and atherosclerotic regression. Initially, we have targeted the ER stress- GSK3α/β pathway by supplementing the drinking water of low-density lipoprotein receptor (Ldlr)-/- mice with the small molecules 4-phenylbutyric acid or valproate. The results suggest that ER stress or GSK3α/β inhibition can attenuate the growth of existing atherosclerotic lesions and appear to increase lesion stability. From this study it remains unclear whether these interventions can promote atherosclerotic regression. Next, to investigate the role(s) of GSK3α/β in pro-atherogenic processes, bone marrow derived macrophages were isolated from myeloid-specific GSK3α- and/or GSK3β-deficient mice. The effects of GSK3α/β-deficiency on signaling pathways regulating atherogenic functions in macrophage were analyzed. This study revealed that GSK3α and GSK3β play distinct, and often opposing roles in macrophage polarization, inflammatory response, lipid accumulation and migration. Furthermore, both GSK3α and GSK3β appear to play redundant roles macrophage viability, proliferation, and metabolism. Lastly, we investigated the effect of macrophage-specific deletion of GSK3α and/or GSK3β on atherosclerotic regression in Ldlr−/− mice. A novel inducible knock out mouse model has been created in which GSK3α and/or GSK3β expression can be ablated by treating the mice with tamoxifen. These mice were fed a high fat diet to promote the development of atherosclerosis, and then mice were treated with tamoxifen to induce GSK3α/β deletion and switched to a chow diet for 12 weeks. All mice were sacrificed at 33 weeks of age and atherosclerotic plaques were analysed. Female mice with induced macrophage-specific GSK3α deficiency, but not GSK3β deficiency, showed regression of existing atherosclerotic lesions. Together, these studies begin to delineate the specific roles of GSK3α and GSK3β in atherosclerotic regression. Furthermore, these data suggest that GSK3α inhibition could be an effective strategy for the treatment of atherosclerotic cardiovascular disease. / Thesis / Doctor of Philosophy (PhD) / Atherosclerosis is a disease involving the build-up of fatty plaques in the arteries, making them hard and narrow, which leads to damage in the heart, coronary or peripheral blood vessels. This can cause acute cardiovascular complications (heart attacks or stroke) and potentially death. We suspect that protein named glycogen synthase kinase (GSK)-3α/β is involved in the development of atherosclerosis. The purpose of this research is to see if we can treat atherosclerosis by blocking GSK3α/β’s functions. The findings of this study demonstrate that blocking GSK3α reduces inflammation, which is a primary cause of atherosclerosis. Furthermore, blocking GSK3α promotes the regression of atherosclerotic plaques and may lower the risk of cardiovascular disease. This knowledge could aid in the development of medications to treat atherosclerosis and reduce the number of individuals who die from heart attacks or strokes.

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La dégénérescence maculaire liée à l'âge (DMLA) est la cause la plus fréquente de déficience visuelle centrale irréversible chez les personnes de plus de 50 ans dans les pays industrialisés, avec des impacts sociétaux et financiers majeurs. La DMLA est une maladie à multiples facettes provoquée par des interactions entre les facteurs de risque et les antécédents génétiques et l'inflammation joue un rôle important. Les effets pro-inflammatoires provoquent une perturbation de l'environnement sousrétinien physiologiquement immunosuppresseur. L'accumulation de phagocytes mononucléaires (PM) dans l'espace sous-rétinien qui s'ensuit est au coeur de l'étiologie des formes atrophiques et humides de la DMLA. Après l’usage de tabac, l'obésité est l'un des facteurs de risque modifiables les plus importants. Nous avons démontré que les régimes riches en graisses exacerbent la néovascularisation choroïdienne (NVC) en modifiant le microbiote intestinal. La dysbiose intestinale entraîne une perméabilité intestinale accrue, une inflammation chronique de bas grade, une augmentation des PM sur le site de l'angiogenèse pathologique dans l'oeil et exacerbe finalement la NVC. La modification du microbiote peut réduire l'inflammation et atténuer la NVC et peut ainsi fournir des traitements peu intrusifs et rentables pour prévenir ou retarder la DMLA exsudative. Une autre option thérapeutique qui pourrait réduire la NVC par modulation inflammatoire consiste à piéger localement les ligands de NRP1 avec un piège dérivé de NRP1. Les ligands de NRP1 sont élevés dans le vitré des patients atteints de DMLA. Nous avons constaté que les PM exprimant NRP1 favorisaient la NVC en atténuant la production de facteurs inflammatoires et en favorisant l'activation alternative, donnant aux PM un caractère pro-angiogénique. Les PM moins inflammatoires et plus de type M2 qui sont enrichis avec l'âge et exacerbent la NVC peuvent être modulés et devenir moins nuisibles en empêchant l'activation de NRP1. Cette thèse explore deux angles dans lesquels la régulation de l'inflammation peut influencer la formation de NVC et jette les bases du développement futur de nouveaux traitements préventifs primaires et secondaires efficaces dans le contexte de la DMLA. / Age related macular degeneration (AMD) is the most common cause of irreversible central vision impairment in people over 50 in industrialized countries, with major societal and financial impacts. AMD is a multifaceted disease provoked by interactions among environmental risk factors and genetic backgrounds in which inflammation plays an important role. Proinflammatory effects cause a disruption of the physiologically immunosuppressive subretinal environment. The ensuing accumulation of mononuclear phagocytes in the subretinal space is central to the etiology of both atrophic and wet forms of AMD. After smoking, obesity is one of the most important modifiable risk factors. We demonstrate that high-fat diets exacerbate choroidal neovascularisation (CNV) by altering gut microbiota. Gut dysbiosis leads to heightened intestinal permeability and chronic low-grade inflammation, increases recruitment of microglia and macrophages to the site of pathological angiogenesis in the eye and ultimately exacerbates CNV. Modifying microbiota can reduce systemic and local choroidal inflammation and attenuate pathological neovascularization and may thus provide minimally intrusive and cost-effective paradigms to prevent or delay exudative AMD. Another therapeutic option that could reduce CNV through inflammatory modulation is locally trapping ligands of NRP1 with a NRP1-derived trap. Ligands for NRP1 are elevated in the vitreous of patients with AMD at times of active CNV. We found that NRP1-expressing MPs promote CNV by mitigating production of inflammatory factors and promoting alternative activation, giving the MPs a pro-angiogenic character. The less inflammatory and more M2-like MPs that are enriched with age and exacerbate CNV can be rendered less detrimental by hindering NRP1 activation. This thesis explores two angles wherein regulation of inflammation can influence the formation of CNV and lays the groundwork for future development of novel effective primary and secondary preventive treatments for AMD.