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Title: | THE HIGH DENSITY LIPOPROTEIN AND ATHEROSCLEROSIS |
Other Titles: | THE DEVELOPMENT OF ATHEROSCLEROSIS AND CORONARY OCCLUSION IN THE MOUSE: INVESTIGATING THE HIGH DENSITY LIPOPROTEIN SIGNALING PATHWAY AND THE IMPACT OF THE SCAVENGER RECEPTOR CLASS B TYPE 1 |
Authors: | Yu, Pei |
Advisor: | Trigatti, Bernardo |
Department: | Biochemistry |
Publication Date: | 2016 |
Abstract: | Coronary artery disease results from atherosclerotic plaque formation. High-density lipoprotein (HDL) has been shown to be inversely associated with the risk of coronary artery disease. It not only reduces lipid accumulation in atherosclerotic plaques by mediating reverse cholesterol transport, but also exerts direct protection on vascular cells via the scavenger receptor class B, type 1 (SR-B1). Increased macrophage apoptosis is commonly observed in advanced or unstable atherosclerotic plaques. In this thesis, the anti-apoptotic effect and the signaling pathway of HDL in macrophages were investigated. We showed that HDL protected macrophages from endoplasmic reticulum (ER) stress induced apoptosis in a SR-B1 adaptor protein PDZK1 and Akt1 dependent manner. Also, atherogenic mice with PDZK1 deficiency in bone marrow-derived cells exhibited increased atherosclerotic plaque sizes with enlarged necrotic cores, which is a feature of rupture-prone plaques. We also found that HDL decreased the proapoptotic Bcl-2 related protein Bim in ER stressed macrophages, and Bim-/- macrophages were resistant to tunicamycin-induced apoptosis. Our in vitro study suggests that Bim is likely to be the downstream factor in the HDL signaling pathway. Consistent with this, inactivation of Bim in vivo significantly reduced plaque area and necrotic core size in a mouse model with low circulating HDL. We also characterized the SR-B1-/-/apoE-/-, a spontaneous coronary heart disease model, by treating them with the clinically used heart disease drug rosuvastatin, and found that rosuvastatin protected SR-B1-/-/apoE-/- mice against atherothrombosis and attenuated myocardial fibrosis and cardiomegaly. This protection may be attributed to the ability of rosuvastatin to reduce oxidized LDL and inhibit macrophage foam cell formation. The work in this thesis contributes to a more detailed understanding of the impacts of HDL and SR-B1 on atherosclerosis. |
URI: | http://hdl.handle.net/11375/18955 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Yu_Pei_finalsubmissionon201603_PhD.pdf | Dissertation | 8.16 MB | Adobe PDF | View/Open |
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