The Role of 15-Lipoxygenase-1- and Cyclooxygenase-2-Derived Lipid Mediators in Endothelial Cell Proliferation

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dc.contributor.advisorDr. Ian A. Blair
dc.contributor.authorWei, Cong
dc.date2023-05-17T03:48:15.000
dc.date.accessioned2023-05-22T16:59:45Z
dc.date.available2010-07-07T00:00:00Z
dc.date.issued2010-08-13
dc.date.submitted2010-07-07T12:00:02-07:00
dc.description.abstractIt is a generally accepted paradigm that there is a direct link between inflammation and tumor progression. During inflammation, there is increased formation of lipid hydroperoxides, mediated either non-enzymatically by reactive oxygen species or enzymatically by lipoxygenases (LOs) or cyclooxygenases (COXs). Lipid hydroperoxides undergo further oxidation into oxo-eicosatetraenoic acids (oxo-ETEs), which are produced and released by cells including macrophages and epithelial cells. Therefore, these oxo-ETEs could potentially mediate biological effects in an autocrine and/or a paracrine manner. In addition, oxo-ETEs conjugate intracellular glutathione (GSH) to form adducts which could serve as biomarkers of oxo-ETE formation. In this study, a targeted lipidomics approach combined with stable isotope dilution methodology was employed to identify and quantify lipid hydroperoxides and their metabolites formed in 15-LO-expressing mouse macrophage cell line (R15L cells) and COX-2 expressing cell models (RIES cells and Caco-2 cells) as well as in mouse hematocytes and primary human monocytes. 15-Oxo-5,8,11,13-(Z,Z,Z,E)-ETE (15-oxo-ETE) was identified and characterized as a major eicosanoid produced in both mouse and human macrophage 15-LO pathway. 15-Oxo-ETE was shown to be a metabolite of arachidonic acid (AA)-derived 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) by 15-hydroxyprostaglandin dehydrogenase (15-PGDH). A novel biological activity of 15-oxo-ETE was revealed, which involved inhibition of human umbilical vein endothelial cell (HUVEC) proliferation by suppressing DNA synthesis, implicating a potential anti-angiogenic role of 15-oxo-ETE. In addition to 15-oxo-ETE, another AA-derived eicosanoid 11-oxo-5,8,12,14-(Z,Z,E,Z)-eicosatetraenoic acid (11-oxo-ETE), was identified as a major metabolite arising from COX-2-derived from 11(R)-hydroxyl-5,8,12,14-(Z,Z,E,Z)-eicosatetraenoic acid (11(R)-HETE) in both rat (RIES) and human (Caco-2) epithelial cell lines. A specific liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM/MS) method revealed that both 11-oxo-ETE and 15-oxo-ETE were secreted in nM concentrations when AA was added to RIES and human Caco-2 cells. Surprisingly, 11(R)-HETE was an excellent substrate for 15-PGDH, with a catalytic efficiency similar to that found for 15(S)-HETE. In addition, it was demonstrated that aspirin significantly stimulated the production of 15(R)-HETE, which was then converted to 15-oxo-ETE by an unknown dehydrogenase (DH). These findings could have significant clinical implications since 15-PGDH is down-regulated during carcinogenesis, which in addition to increasing the pro-proliferative activity of PGE2 would prevent the formation of anti-proliferative 15-oxo-ETE from 15(S)-HETE. However, the formation of 15-oxo-ETE from 15(R)-HETE after aspirin treatment, through a pathway that does not involve 15-PGDH, could help counteract the increased pro-proliferative activity of PGE2.
dc.description.degreeDoctor of Philosophy (PhD)
dc.identifier.urihttps://repository.upenn.edu/handle/20.500.14332/29081
dc.legacy.articleid1265
dc.legacy.fulltexturlhttps://repository.upenn.edu/cgi/viewcontent.cgi?article=1265&context=edissertations&unstamped=1
dc.source.issue219
dc.source.journalPublicly Accessible Penn Dissertations
dc.source.statuspublished
dc.subject.otherLIPID MEDIATORS
dc.subject.other15-LIPOXYGENASE-1
dc.subject.otherCYCLOOXYGENASE-2
dc.subject.otherENDOTHELIAL CELL PROLIFERATION
dc.subject.other15-OXO-ETE
dc.subject.other11-OXO-ETE
dc.subject.otherMedicinal Chemistry and Pharmaceutics
dc.subject.otherPharmacology
dc.titleThe Role of 15-Lipoxygenase-1- and Cyclooxygenase-2-Derived Lipid Mediators in Endothelial Cell Proliferation
dc.typeDissertation/Thesis
digcom.date.embargo2010-07-07T00:00:00-07:00
digcom.identifieredissertations/219
digcom.identifier.contextkey1385106
digcom.identifier.submissionpathedissertations/219
digcom.typedissertation
dspace.entity.typePublication
relation.isAuthorOfPublicationc591d79f-9d97-4bd2-9f4d-c53ab5034f32
relation.isAuthorOfPublication.latestForDiscoveryc591d79f-9d97-4bd2-9f4d-c53ab5034f32
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