Prevention of macrophage apoptosis in advanced atherosclerotic lesions can help stop atherosclerosis progression to vulnerable plaques. High density lipoprotein (HDL) can protect macrophages from apoptosis that has been induced by a variety of agents. We hypothesize that this is the consequence of the sphingolipid, sphingosine-1-phosphate (S1P), specifically carried by HDL, and transferred to S1P receptor 1 (S1P1) on the cells via the HDL receptor, scavenger receptor class B type 1 (SR-B1).
Apoptosis was induced in murine peritoneal macrophages from wild type and different knockout mice with, tunicamycin, thapsigargin, staurosporine, or UV irradiation. Apoptosis was measured by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) or with cleaved caspase-3 (CC3) staining. Treatment of cells with HDL or S1P protected them against apoptosis induced by a variety of stimuli. In contrast, pre-treatment of HDL with S1P lyase, which irreversibly cleaves S1P, eliminated the ability of HDL to protect macrophages. Inhibition of SR-B1’s lipid transport activity reduced HDL dependant protection against apoptosis. Furthermore, HDL dependent protection against apoptosis induced by tunicamycin was prevented when the S1P receptor S1P1 was knocked out. However, this protection was not prevented when apoptosis was induced by staurosporine.
These results suggest that the HDL mediated protection of macrophages against apoptosis is multi-faceted and one approach may involve SR-B1 mediated delivery of S1P from HDL to the S1P1. Understanding the mechanisms by which HDL elicits atheroprotective signalling in macrophages will provide insight into new targets for therapeutic intervention in atherosclerotic disease. / Thesis / Master of Science in Medical Sciences (MSMS) / Atherosclerosis, is a disease where in the artery walls thicken due to cholesterol build-up, is the major underlying cause for cardiovascular diseases, which is currently a leading cause of death in many populations. We believe that HDL, the “good” cholesterol and S1P, a small molecule carried by HDL, can help prevent the progress of atherosclerosis by preventing macrophages, cells that absorb the cholesterol, from dying. We attempt to prove this by providing S1P or HDL to macrophages that are made to undergo cell death. Results show that both HDL and S1P can protect cells against cell death induced by many factors. However, HDL can protect against certain cell death inducing stimuli without the need for S1P and more research is required to fully understand HDL’s protective role in atherosclerosis. Understanding how HDL elicits atheroprotective signalling in macrophages will help in finding new drugs and therapies to reduce atherosclerosis-based deaths across the world.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/27628 |
| Date | January 2019 |
| Creators | Chathely, Kevin |
| Contributors | Trigatti, Bernardo, Medical Sciences (Blood and Cardiovascular) |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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