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http://hdl.handle.net/11375/27839
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DC Field | Value | Language |
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dc.contributor.advisor | Trigatti, Bernardo | - |
dc.contributor.author | Lee, Samuel | - |
dc.date.accessioned | 2022-09-23T20:25:17Z | - |
dc.date.available | 2022-09-23T20:25:17Z | - |
dc.date.issued | 2022 | - |
dc.identifier.uri | http://hdl.handle.net/11375/27839 | - |
dc.description.abstract | Coronary artery disease (CAD) is one of the leading causes of mortality worldwide, and is driven by atherosclerosis development that can lead to occlusive thrombus formation and myocardial infarction. Platelets are known to contribute to atherosclerosis development and thrombosis. Scavenger receptor class B type 1 (SR-B1) deficiency in apolipoprotein E (ApoE) knockout or low-density lipoprotein receptor (LDLR) knockout mice results in occlusive coronary artery atherosclerosis, platelet accumulation in atherosclerotic coronary arteries, and myocardial fibrosis. In this thesis, we examine the effects of genetically inactivating neurobeachin-like 2 (NBEAL2), which has a prominent role in platelet function, on CAD development in SR-B1/ApoE double knockout mice. NBEAL2 deficiency in SR-B1/ApoE double knockout mice reduced aortic sinus and coronary artery atherosclerosis and platelet accumulation in atherosclerotic coronary arteries, but increased myocardial fibrosis levels and reduced survival. NBEAL2 deficiency in SR-B1/ApoE double knockout mice reduced neutrophil granularity and the proportion of myeloperoxidase-positive neutrophils in the myocardium, which may in part contribute to the increased myocardial fibrosis levels. Protease-activated receptor 4 (PAR4) also has a prominent role in platelet function. By using a novel pepducin (RAG8), we examine the effects of pharmacological inhibition of PAR4 on CAD development in high-fat, high-cholesterol, cholate (HFCC) diet-fed SR-B1/LDLR double knockout mice. RAG8 treatment did not alter aortic sinus atherosclerosis levels, but reduced coronary artery atherosclerosis, platelet accumulation in atherosclerotic coronary arteries, and myocardial fibrosis. These protective effects are not dependent on changes in circulating lipids, cytokines, and immune cells, but may be due to reduced vascular cell adhesion 1 (VCAM-1) protein expression in coronary arteries. We also examine the effects of aging on CAD development in HFCC diet-fed SR-B1 single KO mice. Older age in SR-B1 single KO mice did not alter susceptibility to HFCC diet-induced aortic sinus atherosclerosis, but increased susceptibility to HFCC diet-induced coronary artery atherosclerosis, platelet accumulation in atherosclerotic coronary arteries, and myocardial fibrosis. Older-aged SR-B1 KO mice exhibited reduced survival when fed the HFCC diet. These age-dependent changes are not driven by changes in plasma lipids, but likely driven by a combination of increased VCAM-1 protein levels in coronary arteries and circulating cytokines and neutrophils. This thesis demonstrates the potential effects of platelet inhibition and aging on CAD development in mice, and demonstrates that SR-B1 single KO mice may be a versatile and useful diet-inducible mouse model for atherosclerosis studies. Moreover, this thesis highlights the importance of analyzing atherosclerosis at multiple sites and utilizing mice that develop CAD and myocardial fibrosis when investigating the effects of interventions on atherosclerosis and/or CAD development. | en_US |
dc.language.iso | en | en_US |
dc.subject | Atherosclerosis | en_US |
dc.subject | Coronary Artery Disease | en_US |
dc.subject | Platelets | en_US |
dc.subject | Mouse Models | en_US |
dc.subject | Cardiovascular | en_US |
dc.subject | Myocardial Infarction | en_US |
dc.subject | Aging | en_US |
dc.title | Investigating the Potential Effects of Platelet Inhibition and Aging on Coronary Artery Disease Development in Mice | en_US |
dc.type | Thesis | en_US |
dc.contributor.department | Biochemistry and Biomedical Sciences | en_US |
dc.description.degreetype | Dissertation | en_US |
dc.description.degree | Doctor of Philosophy (PhD) | en_US |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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LEE_SAMUEL_K_202209_PHD.pdf | 7.33 MB | Adobe PDF | View/Open |
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