Role of impaired lipid metabolism and immune dysregulation in the pathogenesis of cardiovascular disease
Embargo Date
2024-05-20
OA Version
Citation
Abstract
Cardiovascular disease is the leading cause of death worldwide. Altered lipid metabolism significantly contributes to pathogenesis of cardiovascular disease. Hypercholesterolemia also contributes to elevated oxidative stress, which leads to tissue damage. In my studies, I sought to gain a better understanding on the development of cardiovascular disease in a novel mouse model that mimics human coronary artery disease. This mouse model developed spontaneous occlusive atherosclerosis when placed on atherogenic diet. I found that dual therapy using a nanoparticle carrying an antioxidant agent together with an antiplatelet drug could significantly ameliorate disease progression, compared with groups treated with antioxidant or antiplatelet alone.
In addition to lipid accumulation and oxidative stress, immune modulation has also gained significant attention in the development of cardiovascular disease. Specifically, it has been long observed that cardiovascular disease is one of the major complications in patients with autoimmune disease. To further understand how impaired immune cell functions lead to cardiac dysfunction, I used mouse models of autoimmunity. I found that regulatory T cell (Treg)-specific deletion of a splicing gene, Srsf1, leads to dysfunctional Tregs, which significantly contribute to cardiac dysfunction. I also found that heterozygous deletion of the Srsf1 gene in Tregs significantly delayed disease recovery in a toxin-induced multiple sclerosis model. Transcriptomic analysis of T cells with Srsf1 deficiency showed enrichment in differentially expressed genes that are associated with fatty acid oxidation and lipid metabolism pathways. Using a virus infection model, I also found that Srsf1 deletion in total T cells compromised CD8+ T cell function and monocyte migration. These findings have implications for the role of the splicing gene on cardiovascular disease.
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License
Attribution-NonCommercial-NoDerivatives 4.0 International