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Docosahexaenoic Acid-Mediated Cytotoxicity in Immortalized Cells Open Access


Other title
Docosahexaenoic acid
H9c2 cells
PPAR delta
Epoxydocosapentaenoic acids
Type of item
Degree grantor
University of Alberta
Author or creator
Supervisor and department
Seubert, John M. (Pharmaceutical Sciences)
Examining committee member and department
Leslie, Elaine (Physiology)
Siraki, Arno G. (Pharmaceutical Sciences)
Lavasanifar, Afsaneh (Pharmaceutical Sciences)
Faculty of Pharmacy and Pharmaceutical Sciences
Pharmaceutical Sciences
Date accepted
Graduation date
Master of Science
Degree level
Docosahexaenoic acid (22:6n3, DHA) is an n-3 polyunsaturated fatty acid (PUFA) that is known to induce context-dependent cell survival, as well as apoptosis, but the exact cellular and molecular mechanism(s) remain unknown. DHA is known to act as a natural ligand for the peroxisome proliferator-activated receptors (PPARs) family of nuclear receptor, which may in turn influence cellular death. This thesis focused on the PPAR-mediated mechanistic induction of cell death, involving the accumulation of ceramide in an immortalized cell line treated with DHA. We utilized DHA treatment, with and without a specific inhibitor of PPARδ, GSK 3787. Our results validated PPARδ as a DHA target, which subsequently leads to the production of de novo ceramide, and apoptotic cell death. Various pathways leading to cell death were significantly attenuated with the simultaneous treatment of cells with DHA and GSK 3787, providing evidence that activation of PPARδ is vital to this process. Furthermore, we demonstrate that epoxydocosapentaenoates (EDPs) which are CYP oxidase metabolites of DHA induce a similar signaling pathway culminating in apoptotic cell death, suggesting that they are the active mediators. Our findings thus provide evidence for a novel pathway of DHA-mediated apoptotic cell death, and suggests that EDPs, and in particular 19, 20-EDP play a vital role in this process.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Samokhvalov, V., Zlobine, I. Jamieson, K.L. Jurasz, P.K. Chen, C. Lee, K.S.S. Hammock, B.D.& Seubert, J.M. PPARδ Signaling Mediates the Cytotoxicity of DHA in H9c2 Cells. Toxicology Letters 232: 10-20, 2015.

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