Robichaud, Sabrina2023-11-222023-11-22http://hdl.handle.net/10393/45651http://dx.doi.org/10.20381/ruor-29855Cardiovascular disease is the leading cause of death worldwide. The underlying cause of mortality from cardiovascular disease is the rupture of cholesterol-rich plaques which develops in the artery walls during atherosclerosis. Atherosclerotic plaques are comprised of lipid-laden cells, called foam cells. Overtime, the accumulation of foam cells within the plaque impedes blood flow to the downstream blood vessel. As time progresses, plaque become unstable and at risk of rupture or erosion leading to myocardial infarction, stroke, or death. Current therapies for the treatment of atherosclerosis include cholesterol-lowering drugs which can prevent plaque progression but fail to regress existing plaques in its totality. Autophagy is a highly conserved constitutive cellular process which promotes cellular homeostasis by degrading excess proteins and damaged organelles. It has been previously demonstrated that macrophage autophagy was atheroprotective by reducing inflammation and promoting the clearance of apoptotic cells through efferocytosis. In addition, selective autophagy of lipid droplets, or lipophagy, was demonstrated to account for half of apolipoprotein A-I cholesterol efflux in macrophages foam cells highlighting the importance of functional autophagy during atherosclerosis. The goal of this thesis was to elucidate how autophagy in foam cells participates in atherogenesis with a particular interest in how autophagy controls lipid catabolism to promote the removal of cholesterol from the plaque. The first part of this work uncovered novel receptors important in mediating macrophage foam cell lipophagy. In addition, this study demonstrated that lipid droplets can undergo both macroautophagy and microautophagy. The second part of this work investigated the functionality of autophagy in the two main foam cell population of the atherosclerotic plaque being the macrophage foam cells and the vascular smooth muscle cell foam cells. Unlike macrophages which continue to have functional autophagy at both early and late stages of atherosclerosis, vascular smooth muscle cell foam cells have defective autophagy throughout atherosclerosis progression. Moreover, vascular smooth muscle cells foam cells have a very poor capacity to perform cholesterol efflux. The third part of this work explored how promoting autophagy using trehalose impacted atherosclerosis regression. The promotion of autophagy increased plaque regression in female mice, but not male mice. Altogether, these studies highlighted the critical role of autophagy in maintaining cellular homeostasis to prevent disease progression.enAttribution-NonCommercial 4.0 Internationalhttp://creativecommons.org/licenses/by-nc/4.0/AtherosclerosisAutophagyThesis