Atherosclerosis is a chronic inflammatory disease affecting large- and medium-sized
arteries and is considered the major cause behind cardiovascular diseases (CVD).
Elevated low-density lipoprotein (LDL)-cholesterol and low high-density lipoprotein
(HDL)-cholesterol are considered major risk factors for the CVD. HDL mediates a
variety of atheroprotective actions, many of them involving the interaction with the
scavenger receptor class B, type 1 (SR-B1).
Despite the efforts placed in raising HDL-cholesterol, no improvement has been
achieved in reducing CVD risk, suggesting that other components of the HDL particles
may be responsible for HDL-mediated atheroprotection. One of these may be
sphingosine-1-phospate (S1P).
In this thesis, the role of S1P receptors (S1PRs) in atherosclerosis is explored,
with emphasis in macrophage apoptosis. In particular, the importance of the macrophage
S1PR1 and its role in apoptosis and atherosclerosis was evaluated. We demonstrated that
diabetes exacerbates atherosclerosis development and myocardial infarction in SR-B1
KO/apoE-hypomorphic mice and that treatment with FTY720, a S1PR agonist, protects
against diabetes pro-atherogenic effects. We also show that S1PR1 agonists protected
macrophages against apoptosis through phosphoinositide 3-kinase (PI3K)/AKT, and that
HDL failed to protect S1PR1 deficient macrophages against apoptosis. In vivo,
macrophage S1PR1 deficiency translated into increased atherosclerosis, necrotic core
formation and numbers of apoptotic cells in the atherosclerotic plaque.
BIM deficiency in BM cells was protective against atherosclerosis development
and HDL treatment reduced BIM protein levels in cells exposed to ER stressors,
suggesting that the pro-apoptotic protein may be an important target for HDL in
macrophages.
We conclude that signaling through the S1PRs, in particular S1PR1 is important
in controlling macrophage apoptosis and atherosclerosis development. Our data suggests
that S1PR1 signaling axis and the pro-apoptotic protein BIM play an important role in
mediating HDL anti-apoptotic signaling, however further studies are required to clarify
the interaction between all of these factors. / Thesis / Doctor of Philosophy (PhD)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/20796 |
| Date | January 2016 |
| Creators | Gonzalez Jara, Leticia A |
| Contributors | Trigatti, Bernardo L, Biochemistry and Biomedical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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