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This Article Full Text Full Text (PDF) All Versions of this Article: 290/5/H1777    most recent 01087.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (26) Citing Articles via Google Scholar Google Scholar Articles by Landar, A. Articles by Darley-Usmar, V. M. Search for Related Content PubMed PubMed Citation Articles by Landar, A. Articles by Darley-Usmar, V. M.

Interaction of electrophilic lipid oxidation products with mitochondria in endothelial cells and formation of reactive oxygen species

¹Department of Pathology, ²Center For Free Radical Biology, ³Department of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, Alabama; Departments of ⁴Pharmacology and ⁵Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; and ⁶Department of Organic Chemistry, University of Pavia, Pavia, Italy

Submitted 13 October 2005 ; accepted in final form 21 December 2005

Electrophilic lipids, such as 4-hydroxynonenal (HNE), and the cyclopentenones 15-deoxy-^12,14-prostaglandin J₂ (15d-PGJ₂) and 15-J₂-isoprostane induce both reactive oxygen species (ROS) formation and cellular antioxidant defenses, such as heme oxygenase-1 (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, dichlorofluorescein 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 by using a fluorescently labeled nonelectrophilic lipid. The role of mitochondria was confirmed by 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.

15-deoxy-^12,14-prostaglandin J₂; isoprostane; cyclopentenone; 4-hydroxynonenal; atherosclerosis; rho0

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