Oxidized phospholipids containing arachidonic acid, (Ox-PAPC) one of which is PEIPC, have been shown to accumulate in atherosclerotic lesions, apoptotic cells, and other sites of chronic inflammation. Ox-PAPC and specifically PEIPC also play a key role in the pro-inflammatory activation of endothelial cells, a key event in the initiaton and progression of atherosclerosis. We have synthesized EI, the fatty acid oxidation product present in PEIPC, and have shown some overlap in regulation of gene expression by the two molecules. However, some exciting preliminary data suggest that EI inhibits some of the pro-atherogenic genes that PEIPC upregulates in human aortic endothelial cells (HAECs). Furthermore EI also inhibits the regulation of at least two of these genes by IL1?.
In Aim 1 we will determine the importance of EI as an anti-inflammatory molecule. A major goal of these studies is to identify proteins that mediate EI regulation of inflammation. We will isolate protein that bind EI and PEIPC in HAECs and identify these proteins by ESI/MS. Then we will validate their importance in regulating inflammation using siRNA. We have identified several candidates for testing and will screen other proteins that bind PEIPC and EI for additional candidates. We will be guided in this search by our microarray analysis of EI vs PEIPC treated HAECs and by studies of 147 donor endothelial cells differentially regulated by Ox-PAPC. This study will further our understanding of the mechanism of oxidized fatty acid and phospholipid gene regulation and provide insight that will be useful in drug discovery and development of inflammatory inhibitors.
Oxidized phospholipids and specifically PEIPC have been demonstrated to be important mediators of the inflammatory response in the endothelium, concentrated in atherosclerotic lesions and other sites of chronic inflammation. In the proposed research we will determine the role of an oxidized fatty acid with similar structure, EI, in the regulation of inflammation in endothelial cells, an important biological pathway in the development of heart disease. This work is in accordance to the NIH's mission to develop fundamental knowledge to enhance health and reduce the burdens of illness and disability and will provide valuable insight for the discovery and development of novel therapeutics to treat this disease.
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