Dysregulated toll-like receptor mechanisms: the cause of atherosclerosis?

Gamper, Frederick (2011) Dysregulated toll-like receptor mechanisms: the cause of atherosclerosis? Doctoral thesis (DPhil), University of Sussex.

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It is estimated that in the European Union 2 million deaths each year (42% of total) are as a result of cardiovascular disease, of which atherosclerosis is a major underlying factor. In 2006 this was estimated to cost the European Union an astonishing €192 billion. Once considered a lipid storage disorder it is becoming apparent that atherosclerosis is in fact due to an inflammatory dysfunction, with a number of endogenous and exogenous activators coming to light. The process of atheroma formation is poorly understood. This study seeks to discover the underlying mechanisms of plaque development with the view to develop novel therapeutics for this disease.

Our results demonstrate a modulatory role of endogenous low density lipoprotein (LDL), “bad cholesterol”, on bacterial infections. Using primary human umbilical vein endothelial cells (HUVECs) I have shown that “non-self” oxidised LDL can reduce cell surface expression of pattern recognition receptors (PRRs) of the innate immune system, causing modulation of the cellular response directed towards atherosclerosis-associated bacterial pathogen-associated molecular patterns (PAMPs). Triple label fluorescent confocal microscopy of HUVECs revealed altered trafficking and targeting of PRRs of the innate immune system when endogenous LDL were combined with a bacterial infection in comparison to infection alone, indicating a source of the inflammatory dysfunction observed in this disease. This study illustrates that oxidatively modified LDL has a profound effect on bacterial infection, dramatically altering cellular response which may begin to explain the root cause of atherosclerosis. Through experimentation with human embryonic kidney (HEK) transfectants and HUVEC PRR silencing this study uncovered lipid raft dependant Toll-like receptors (TLRs) as fundamental culprits of this multi-factorial disease, with emphasis on TLR2 and TLR4. Future therapy designed for atherosclerosis will unquestionably involve the manipulation of TLR signalling.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0581 Specialties of internal medicine
Depositing User: Library Cataloguing
Date Deposited: 28 Jun 2011 08:36
Last Modified: 14 Aug 2015 12:55
URI: http://sro.sussex.ac.uk/id/eprint/6904

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