ORCID
https://orcid.org/0000-0003-3376-1300
Date of Award
1-10-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Cardiovascular diseases, particularly atherosclerosis, pose significant health concerns, necessitating a comprehensive understanding of underlying mechanisms for effective therapeutic interventions. In this dissertation, I studied diverse topics, ranging from dietary impacts to intracellular processes, shedding light on novel avenues for atherosclerosis research. It is divided in 4 core projects. In Chapter 2) I studied how dietary protein drives atherosclerosis and lesion complexity. We found that protein ingestion acutely elevates amino acid levels in blood and atherosclerotic plaques, stimulating macrophage mTOR signaling. This is causal in plaque progression as the effects are abrogated in macrophage-specific Raptor-null mice. Mechanistically, we find amino acids exacerbate macrophage apoptosis induced by atherogenic lipids, a process that involves mTORC1-dependent inhibition of mitophagy, accumulation of dysfunctional mitochondria, and mitochondrial apoptosis. In Chapter 3), building on our previous work emphasizing the role of amino acids in macrophage mTORC1 signaling and plaque progression, we now investigate the synergistic impact of lipids and amino acids. We confirmed LDL and cholesterol as inducers of macrophage mTORC1 signaling while co-treatment of LDL and leucine lead to a synergistic activation. Similar effects were observed in atherogenic lipids. Our in vitro studies demonstrated that lipid-amino acid co-treatment exerts synergistically inhibits autophagy. In Chapter 4), we directed our focus to macrophage impaired lysosomes, which contribute to plaque progression, suggesting an atheroprotective potential through lysosomal repair. Galectin-3 (Gal3) recognizes and repairs damaged lysosomes in atherogenic macrophages. We demonstrated Gal3's protective role in Gal3-KO macrophages, which exhibiting higher sensitivity to damaging agents, reduced autophagy, increased inflammation, impaired repair mechanisms and higher rates of cell death. In our vivo study, Gal3-deficient mouse had increased plaque size and altered plaque composition. Overall, our data demonstrate important roles for Gal3 in macrophage lysosome repair mechanisms which are a critical response against atherosclerosis. And lastly, in Chapter 5) using macrophage-specific Rictor- and mTOR-deficient mice, we dissected the distinct functions of mTORC2 pathways in atherogenesis. Macrophage-specific mTORC2-deficient mice exhibits larger, more complex lesions and increased cell death. In cultured macrophages, mTORC2 inhibits FoxO1 transcription factor, leading to suppression of proinflammatory pathways. Interestingly, collective deletion of macrophage mTOR, which ablates mTORC1- and mTORC2-dependent pathways, leads to minimal change in plaque size or complexity, reflecting the balanced yet opposing roles of these signaling arms. Collectively, these projects contribute to a holistic understanding of atherosclerosis and offer promising avenues for therapeutic interventions.
Language
English (en)
Chair and Committee
Joel Schilling
Committee Members
Babak Razani
Recommended Citation
Rodriguez Velez, Astrid Carolina, "The Macrophage Autophagy-Lysosome System in Atherosclerosis Pathogenesis" (2024). Arts & Sciences Electronic Theses and Dissertations. 3217.
https://openscholarship.wustl.edu/art_sci_etds/3217