Effect of Oxidation on Rate of ApoA-I - HDL Exchange
Abstracts
Initial Award Abstract |
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Tobacco smoke exposure is a major risk factor for cardiovascular diseases. One of the reasons why tobacco smoke can cause deleterious effects on the circulatory system is because of the chronic inflammation state that affects smokers. This inflammatory burden is a major cause of atherosclerosis in smokers. Chronic inflammation gives rise to the expression of enzymes which produce highly oxidative compounds as part of an immune response regimen. Myeloperoxidase (MPO) is the primary enzyme involved in this process. The reactive compounds generated by activated MPO damage proteins and lipids and by this contributes to the initiation and progression of atherosclerosis. High density lipoprotein (HDL - the "good" cholesterol) is an important anti-atherogenic factor but interestingly a target of MPO-mediated oxidation. These particles normally transport insoluble lipids and cholesterol in the bloodstream to the liver, thanks to the unique properties of a protein called apolipoprotein A-I (apoA-I). If the normal function of apoA-I and HDL is affected, excess cholesterol can accumulate in the walls of blood vessels promoting atherosclerosis. Since oxidized high density lipoprotein are found in the site of atherosclerosis lesions and oxidation of HDL impairs its anti-atherogenic function of cholesterol transport, it can be concluded that tobacco smoke-induced oxidation of HDL constitute a contributing factor to progression of atherosclerosis. The goal of our research is to investigate the molecular mechanism underlying the atherogenic effects of oxidative stress, namely those arising from long term exposure to tobacco smoke. The central hypothesis of this proposal is that oxidative modification of HDL in tobacco smokers is a major contributor to the development of atherosclerosis and, in particular, that oxidation of apoA-I in HDL, impairs its ability of efficiently uptake and release lipid and cholesterol. To test this hypothesis we have recently developed a fluorescence-based assay to measure in real time apoA-I exchange rates on and off HDL. Thanks to this innovative assay we will test the effect of MPO induced oxidation on the rate of exchange of apoA-I on and off HDL. Using variations of apoA-I that are resistant to oxidation, we will determine whether oxidation resistance imparts retention of exchangeability on and off HDL. Findings obtained from this research will significantly contribute to understanding the molecular mechanism linking tobacco smoke-related oxidative stress and its associated cardiovascular diseases and will be useful in the design of therapeutic strategies to decrease lipoprotein damage caused by tobacco smoke exposure. |
Publications
| The Interplay between Size, Morphology, Stability and Functionality of High Density Lipoprotein Subclasses |
| Periodical: Biochemistry |
Index Medicus: |
| Authors: Cavigiolio, G., Shao, B., Geier, E.G., Heinecke, J.W., Oda, M.N. |
ART |
| Yr: 2008 |
Vol: 47 |
Nbr: |
Abs: |
Pg: 4770-4779 |
| The Interplay between Size, Morphology, Stability and Functionality of High Density Lipoprotein Subclasses |
| Periodical: Biochemistry |
Index Medicus: |
| Authors: Cavigiolio, G., Shao, B., Geier, E.G., Heinecke, J.W., Oda, M.N. |
ART |
| Yr: 2008 |
Vol: 47 |
Nbr: |
Abs: |
Pg: 4770-4779 |
