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1 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA
2 Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL, USA
3 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
4 Department of Pharmacology, Vanderbilt University, Nashville, TN, USA
5 Department of Organic Chemistry, University of Pavia, Pavia, Pavia, Italy
6 Department of Pharmacology, Vanderbilt University, Nashville, TN, USA; Department of Medicine, Vanderbilt University, Nashville, TN, none
* To whom correspondence should be addressed. E-mail: darley{at}path.uab.edu.
Electrophilic lipids such as 4-hydroxynonenal (HNE), and the cyclopentenones 15-deoxy-
12,14-prostaglandin J2 (15d-PGJ2) and 15-J2-isoprostane (15-J2-IsoP) induce both reactive oxygen species (ROS) formation and cellular antioxidant defenses such as heme oxygenase (HO-1) and glutathione (GSH). When we compared the ability of these distinct electrophiles to stimulate GSH and HO-1 production, the cyclopentenone electrophiles were somewhat more potent than HNE. Over the concentration range required to observe equivalent induction of GSH, DCF fluorescence was used to determine both the location and amounts of electrophilic lipid-dependent ROS formation in endothelial cells. The origin of the ROS on exposure to these compounds was largely mitochondrial. To investigate the possibility that the increased ROS formation was due to mitochondrial localization of the lipids, we prepared a novel fluorescently labeled form of the electrophilic lipid 15d-PGJ2. The lipid demonstrated strong colocalization with the mitochondria, an effect which was not observed using a fluorescently labeled non-electrophilic lipid. The role of mitochondria was confirmed using cells deficient in functional mitochondria. On the basis of these data we propose that ROS formation in endothelial cells is due to the direct interaction of these lipids with the organelle.
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