Atherosclerosis is a major cause of cardiovascular disease, which is among the leading causes of death globally. Elevated plasma concentration of low density lipoprotein (LDL) cholesterol is a risk factor for atherosclerosis, while a high plasma level of high density lipoprotein (HDL) cholesterol is considered protective. Uptake of HDL cholesterol by hepatocytes during reverse cholesterol transport, and athero-protective signaling induced by HDL in other cells are mediated by the scavenger receptor class B, type 1 (SR-B1).
SR-B1 deficiency in mice that are susceptible to atherosclerosis results in exacerbation of atherosclerosis, and in mice with mutations in apolipoprotein E (apoE), renders mice uniquely susceptible to occlusive coronary artery (CA) atherosclerosis and myocardial infarction.
In this thesis, the impact of a lack of SR-B1 on the development of atherosclerosis is characterized in otherwise wild type mice, and in mice that also lack the LDL receptor (LDLR). We demonstrate that after prolonged feeding of a high fat, high cholesterol cholate-containing diet, SR-B1 knockout (KO) mice develop similar levels of diet-induced atherosclerosis to LDLR KO mice and apoE KO mice in traditionally susceptible arteries, and significantly more atherosclerosis in arteries that are typically resistant to plaque development, such as the CAs. SR-B1/LDLR double KO mice develop extensive occlusive CA atherosclerosis accompanied by myocardial infarction, and exhibit reduced
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survival compared to LDLR KO control mice when fed a variety of atherogenic diets.
In both SR-B1 single KO and SR-BI/LDLR dKO mice, CA atherosclerosis is accompanied by splenomegaly, elevated numbers of circulating leukocytes and increased expression of VCAM-1 in CA endothelium. Interestingly, removal of the spleen has no effect on circulating leukocyte numbers or atherosclerosis in SR-B1/LDLR dKO mice, suggesting the enlarged spleens in SR-B1 deficient mice do not influence atherosclerosis in these animals.
We conclude that SR-B1 is important for the protection against atherosclerosis in mice, particularly in CAs. This is likely through roles in multiple cell types including hepatocytes, endothelial cells and bone marrow-derived cells. Future studies should focus on evaluating the impact of cell-specific SR-B1 activity in different cell types on murine atherosclerotic CA disease. / Thesis / Doctor of Philosophy (PhD)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/18073 |
| Date | January 2015 |
| Creators | Fuller, Mark |
| Contributors | Trigatti, Bernardo, Biochemistry and Biomedical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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