It is now recognized that lipid oxidation produces an array of compounds capable of initiating redox cell signaling. Some of the pathways induce apoptosis while others induce the synthesis of proteins which increase the threshold at which oxidative stress and cytotoxicity occurs. Understanding how these responses are distinguished is critical in determining the molecular events that protect the cell against oxidative damage mediated by xenobiotics or during the pathophysiology of disease. In the previous funding period the central focus of this proposal was to define the mechanisms through which oxidized lipids adapt the endothelial cell to oxidative stress using the induction of the intracellular antioxidant glutathione (GSH) as a model. Preliminary data and published observations developed through the previous funding period identified mechanisms through which a specific sub-class of oxidized lipids, those with electrophilic reactive carbon centers, mediate signal transduction. We found that cytoprotection was dependent on the activation of the electrophile response element (also known as the antioxidant response element) which induces the synthesis of cytoprotective proteins such as heme oxygenase and glutamyl cysteine ligase. In the course of these studies we have used a proteomics approach to define the subset of proteins reactive to electrophilic lipids in the cell which we have designated as the electrophile responsive proteome. These data have led to the hypothesis that electrophilic lipids generated during lipid peroxidation control cell function through modification of the proteins that compose the electrophilic responsive proteome. This hypothesis will be tested by pursuit of the following Specific Aims: 1) Determine whether distinct classes of lipid derived electrophilic cyclopentenones react with different members of the electrophile responsive proteome 2) Determine the effect of the activation of endogenous enzymatic sources of lipid oxidation products on the electrophile responsive proteome. 3) Determine the functional impact of the interaction of electrophilic lipids with endothelial cell mitochondria. The information gained from the accomplishment of these specific aims will give insight into the mechanisms of adaptation and cytotoxicity of the endothelium under toxicological and pathological stress.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES010167-09
Application #
7414397
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Nadadur, Srikanth
Project Start
2000-05-01
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
9
Fiscal Year
2008
Total Cost
$214,106
Indirect Cost
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Dodson, Matthew; Darley-Usmar, Victor; Zhang, Jianhua (2013) Cellular metabolic and autophagic pathways: traffic control by redox signaling. Free Radic Biol Med 63:207-21
Cummins, Timothy D; Higdon, Ashlee N; Kramer, Philip A et al. (2013) Utilization of fluorescent probes for the quantification and identification of subcellular proteomes and biological processes regulated by lipid peroxidation products. Free Radic Biol Med 59:56-68
Higdon, Ashlee; Diers, Anne R; Oh, Joo Yeun et al. (2012) Cell signalling by reactive lipid species: new concepts and molecular mechanisms. Biochem J 442:453-64
Darley-Usmar, Victor M; Ball, Lauren E; Chatham, John C (2012) Protein O-linked *-N-acetylglucosamine: a novel effector of cardiomyocyte metabolism and function. J Mol Cell Cardiol 52:538-49
Higdon, Ashlee N; Benavides, Gloria A; Chacko, Balu K et al. (2012) Hemin causes mitochondrial dysfunction in endothelial cells through promoting lipid peroxidation: the protective role of autophagy. Am J Physiol Heart Circ Physiol 302:H1394-409
Hill, Bradford G; Benavides, Gloria A; Lancaster Jr, Jack R et al. (2012) Integration of cellular bioenergetics with mitochondrial quality control and autophagy. Biol Chem 393:1485-1512
Higdon, Ashlee N; Landar, Aimee; Barnes, Stephen et al. (2012) The electrophile responsive proteome: integrating proteomics and lipidomics with cellular function. Antioxid Redox Signal 17:1580-9
Giordano, Samantha; Lee, Jisun; Darley-Usmar, Victor M et al. (2012) Distinct effects of rotenone, 1-methyl-4-phenylpyridinium and 6-hydroxydopamine on cellular bioenergetics and cell death. PLoS One 7:e44610
Sansbury, Brian E; Jones, Steven P; Riggs, Daniel W et al. (2011) Bioenergetic function in cardiovascular cells: the importance of the reserve capacity and its biological regulation. Chem Biol Interact 191:288-95
Diers, Anne R; Broniowska, Katarzyna A; Darley-Usmar, Victor M et al. (2011) Differential regulation of metabolism by nitric oxide and S-nitrosothiols in endothelial cells. Am J Physiol Heart Circ Physiol 301:H803-12

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