Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)


Food Technology

Committee Chair/Advisor

Dr. Alexis Stamatikos

Committee Member

Dr. Vivian Haley-Zitlin

Committee Member

Dr. Elliot Jesch

Committee Member

Dr. Kimberly Paul


Atherosclerosis is a condition caused by cholesterol accumulating in arterial intimal cells and is a disease that kills more people in the United States and globally than any other disease. Atherosclerosis is commonly recognized to arise from arterial intimal macrophage cholesterol accumulation, but cell lineage tracing technology has shown that a large majority of cholesterol-laden intimal cells found in atherosclerotic arteries are actually vascular smooth muscle cells that have switched phenotypes to a macrophage-like cell. This vascular smooth muscle cell to macrophage-like cell phenotypic switch is known as transdifferentiation and can be triggered by vascular smooth muscle cell cholesterol accumulation. While vascular smooth muscle cell to macrophage-like cell transdifferentiation is considered pro-atherogenic, mechanisms that govern this process are not entirely elucidated. Furthermore, lipid-laden macrophage-like cells of vascular smooth muscle cell origin have demonstrated impaired ABCA1-dependent cholesterol efflux, but it is poorly understood why this occurs in these cholesterol-filled cells. A possible mechanism, which may at least partially attribute to lipid-filled macrophage-like cells demonstrating attenuated ABCA1-dependent cholesterol efflux, is miR-33a expression, as a primary function of this microRNA is to silence ABCA1 expression, but this has yet to be rigorously investigated. For me to directly test this, I would need to identify an immortalized vascular smooth muscle cell line that modulates cholesterol homeostasis and transdifferentiates into macrophage-like cells when exposed to high cholesterol levels, similar to primary vascular smooth muscle cells. I characterized the vascular smooth muscle cell line MOVAS cells to determine that this cell line regulates cholesterol metabolism and responds to hypercholesterolemic conditions, similar to primary vascular smooth muscle cells. Thus, the MOVAS cell line was used to generate miR-33a knockout MOVAS cells to compare to miR-33a endogenously expressing wild-type MOVAS cells to delineate any possible pro-atherogenic role of miR-33a expression in cultured vascular smooth muscle cells. When these two types of MOVAS cells were cholesterol-loaded to convert into macrophage-like cells, this resulted in the wild-type MOVAS cells exhibiting impaired ABCA1-dependent cholesterol efflux. In the cholesterol-loaded wild-type MOVAS macrophage-like cells, I also observed a delayed restoration of vascular smooth muscle cell phenotype when these cells were exposed to the ABCA1 cholesterol acceptor, apoAI. My results imply that miR-33a expression in vascular smooth muscle cells drives atherosclerosis by triggering macrophage-like cell transdifferentiation via attenuated ABCA1-dependent cholesterol efflux. Based on my findings, testing the potential pro-atherogenic impact of vascular smooth muscle cell miR-33a expression in atherogenic animal models is warranted.



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