Ma, KL;
(2008)
A study of the anti-atherosclerotic and anti-inflammatory effects of Sirolimus.
Doctoral thesis , UCL (University College London).
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Abstract
Inflammation accelerates the progression of atherosclerosis. Sirolimus, a potent immunosuppressive agent, has been shown with pleiotropic antiatherosclerotic effects. This study was to explore potential anti-atherosclerotic mechanisms of Sirolimus using cell culture studies and apolipoprotein E knockout (apoE KO) mice under inflammatory stress. Results showed that Sirolimus decreased cholesterol accumulation caused by inflammatory stress in human vascular smooth muscle cells (VSMCs), macrophages, and human hepatoblastoma cell line (HepG2). Sirolimus decreased formation of atherosclerotic plaques in the aortas of inflamed apoE KO mice. Sirolimus inhibited the mRNA expression of sterol regulatory element-binding protein (SREBP) cleavage activating protein (SCAP) and SREBP-2, and decreased translocation of SCAP/SREBP-2 complex from endoplasmic reticulum (ER) to Golgi in VSMCs and HepG2 cells in the presence of IL-1 3, thereby overriding IL-lp induced transcription of LDL receptor (LDLr) and 3-hydroxy-3-methyglutaryl coenzyme A reductase (HMGR). Insulin induced gene-1 (Insig-1) is a retention factor of SCAP in the ER and modulates HMGR degradation at posttranscriptional level. Interestingly, Sirolimus accelerated HMGR degradation by up-regulating Insig-1 expression in VSMCs. Sirolimus also reversed the reduction of cholesterol efflux induced by inflammatory stress through ATP-binding cassette transporter Al (ABCA1) mediated pathway. This was mediated by increasing the gene and protein expression of ABCA1, peroxisome proliferator-activated receptor-a (PPARa), and liver X receptor-a (LXRa) both in vitro and in vivo studies. Sirolimus also directly inhibited the production of inflammatory cytokines shown in our experiments. Taken together, both in vivo and in vitro findings demonstrated that Sirolimus ameliorated cholesterol homeostasis disrupted by inflammatory stress, which was through multiple pathways. Sirolimus down-regulated LDLr-mediated cholesterol influx, down-regulated HMGR-mediated cholesterol biosynthesis, and up-regulated ABCA1 -mediated cholesterol efflux. Furthermore, Sirolimus inhibited the production of inflammatory cytokines. Our studies for the first time indicate that Sirolimus has very pronounced anti-inflammatory properties and highly beneficial anti-atherosclerosis effects expressed through rebalancing disrupted intracellular cholesterol homeostasis involving various molecular mechanisms.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | A study of the anti-atherosclerotic and anti-inflammatory effects of Sirolimus |
| Identifier: | PQ ETD:593575 |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest. Third party copyright material has been removed from the ethesis. Images identifying individuals have been redacted or partially redacted to protect their identity. |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1446240 |
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