doi: 10.1161/hq1101.098488
© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Biphasic Effects of 15-Deoxy-
12,14-Prostaglandin J2 on Glutathione Induction and Apoptosis in Human Endothelial Cells
From the Department of Pathology, Molecular and Cellular Division (A.-L.L., D.R.M., V.M.D.-U.), Center for Free Radical Biology (H.J.F., V.MD-U), and the Department of Environmental Health Sciences, School of Public Health (D.A.D., H.J.F.), University of Alabama at Birmingham, and the Department of Pharmacology (R.T.M), University of Wisconsin-Madison.
Correspondence to Dr Victor M. Darley-Usmar, Department of Pathology, Molecular and Cellular Division, University of Alabama at Birmingham, Volker Hall Room G038, 1670 University Blvd, Birmingham, AL 35294-0019. E-mail darley{at}path.uab.edu
Abstract—— The lipid products derived from the cyclooxygenase pathway can have diverse and often contrasting effects on vascular cell function. Cyclopentenone prostaglandins (cyPGs), such as 15-deoxy-
12,14-prostaglandin-J2 (15d-PGJ2), a peroxisome proliferator–activated receptor-
(PPAR) agonist, have been reported to cause endothelial cell apoptosis, yet in other cell types, cyPGs induce cytoprotective mediators, such as heat shock proteins, heme oxygenase-1, and glutathione (GSH). Herein, we show in human endothelial cells that low micromolar concentrations of 15d-PGJ2 enhance GSH-dependent cytoprotection through the upregulation of glutamate-cysteine ligase, the rate-limiting enzyme of GSH synthesis, as well as GSH reductase. The effect of 15d-PGJ2 on GSH synthesis is attributable to the cyPG structure but is independent of PPAR, inasmuch as the other cyPGs, but not PPAR or PPAR
agonists, are able to increase GSH. The increase in cellular GSH is accompanied by abrogation of the proapoptotic effects of 4-hydroxynonenal, a product of lipid peroxidation present in atherosclerotic lesions. However, higher concentrations of 15d-PGJ2 (10 µmol/L) cause endothelial cell apoptosis, which is further enhanced by depletion of cellular GSH by buthionine sulfoximine. We propose that the GSH-dependent cytoprotective pathways induced by 15d-PGJ2 contribute to its antiatherogenic effects and that these pathways are distinct from those leading to apoptosis.
Key Words: cyclopentenone prostaglandins • glutathione • glutamate-cysteine ligase • endothelium • apoptosis
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