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

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The Role of 15-Lipoxygenase-1- and Cyclooxygenase-2-Derived Lipid Mediators in Endothelial Cell Proliferation University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations Summer 2010 The Role of 15-Lipoxygenase-1- and Cyclooxygenase-2-Derived Lipid Mediators in Endothelial Cell Proliferation Cong Wei University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Medicinal Chemistry and Pharmaceutics Commons, and the Pharmacology Commons Recommended Citation Wei, Cong, "The Role of 15-Lipoxygenase-1- and Cyclooxygenase-2-Derived Lipid Mediators in Endothelial Cell Proliferation" (2010). Publicly Accessible Penn Dissertations. 219. https://repository.upenn.edu/edissertations/219 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/219 For more information, please contact [email protected]. The Role of 15-Lipoxygenase-1- and Cyclooxygenase-2-Derived Lipid Mediators in Endothelial Cell Proliferation Abstract It 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 similaro t 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. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) First Advisor Dr. Ian A. Blair Keywords LIPID MEDIATORS, 15-LIPOXYGENASE-1, CYCLOOXYGENASE-2, ENDOTHELIAL CELL PROLIFERATION, 15-OXO-ETE, 11-OXO-ETE Subject Categories Medicinal Chemistry and Pharmaceutics | Pharmacology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/219 THE ROLE OF 15-LIPOXYGENASE-1- AND CYCLOOXYGENASE-2-DERIVED LIPID MEDIATORS IN ENDOTHELIAL CELL PROLIFERATION Cong Wei A DISSERTATION In Pharmacological Sciences Presented to the Faculties of the University of Pennsylvania In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2010 Supervisor of Dissertation _____________________ Ian A. Blair, Ph.D. A. N. Richards Professor of Pharmacology Graduate Group Chairperson _____________________ Vladimir R. Muzykantov, M.D., Ph.D. Associate Professor of Pharmacology and Medicine Dissertation Committee Harry Ischiropoulos, Ph.D., Research Professor of Pediatrics and Pharmacology Ellen Puré, Ph.D., Professor of Pharmacology George H. Rothblat, Ph.D., Professor of Pediatrics Alexander Steven Whitehead, Ph.D., Professor of Pharmacology DEDICATION On the last day before I came to the United States for my Ph.D. study, I learned the names of my grandparents. This thesis is dedicated to them and my beloved parents Ziqing Wei & Shuzhen Li Lianren He & Weiben Zhou and Ruidong Wei & Xinglin He ii ACKNOWLEDGMENTS I give endless thanks to my thesis advisor and mentor Dr. Ian A. Blair, who has provided me with tremendous inspiration, guidance, and support. His wisdom, generosity and scientific knowledge have been instilled into my Ph.D. journey to make it an extremely great experience, and will continuously boost my motivation in my future career. I would like to thank all the past and current members of Blair lab for their advice, support and friendship over the years. I owe particular thanks to Drs. Wenying Jian, Seon Hwa Lee, and Peijuan Zhu who have brought me and trained me in the field of biomarkers and LC-MS since the very beginning. I am especially grateful to Drs. Suhong Zhang and Jasbir Arora who have generously provided their expertise to help with my studies. I am also grateful to Dr. Clementina Mesaros, with whom I shared with a lot of trouble-shooting on the instruments. I would like to give special thanks to Xiaojing Liu and Catherine Huang who provided generous assistance on the completion of my work. Without all the help and support, my thesis work would not be possible. I am particularly grateful to my dissertation committee chair Dr. Harry Ischiropoulos, who has provided me with his invaluable insight, suggestions and support since before my preliminary exam. I would like to thank Dr. Ellen Puré and Dr. George Rothblat for being my committee members giving constructive advice and the pleasant research collaborations. I would also like to thank Dr. Steve Whitehead for his time and support through my studies. iii I am so grateful to Dr. Tian J. Yang for his generous support to my thesis studies during my internship at Hoffman-La Roche. I would like to thank Dr. Vladimir Muzykantov and Dr. Vladimir Shuvaev for providing important materials as well as their inspiring suggestions for my studies. I would also like to thank Dr. Klaus Kaestner for his training during my laboratory rotation and the ongoing support. I would like to thank Christine Shwed, Linda LeRoy, Mary Scott and Sarah Squire for their help throughout the years in the Pharmacology Program at Penn. I have been graced with incredible friendships during my time here, and I am very grateful to all my friends and relatives during my Ph.D. journey. Special thanks go to Dr. Diana Ye and her husband Bruce Au, Dr. Michael Pollack and his wife Judith, Jie Gao and his wife Mei Long, Jiansheng Huang and his wife Qi Wu, Minhao Xue and her husband John McGurk, Stefanie Khartulyari, Dr. Arnaldo Diaz, Dr. Xuan Dai, Dr. Ginny Weibel, Michelle Joshi, Dr. Michelle Kinder, Zhuo Ye, Jing Hu, Yun Wang, Michelle Chang, Hongmei Li, and Mei Liu. Their help, caring about me, sharing ups and downs with me as well as all the fun time together have helped me go through the graduate life more easily. Last but not least, I am deeply indebted to my parents Ruidong Wei and Xinglin He. Their unconditional love and always being there supporting have led me to the science palace, and made my Ph.D. journey much more meaningful. iv ABSTRACT THE ROLE OF 15-LIPOXYGENASE-1- AND CYCLOOXYGENASE-2-DERIVED LIPID MEDIATORS IN ENDOTHELIAL CELL PROLIFERATION Cong Wei Ian A. Blair, Ph.D. Supervisor of Dissertation It 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 v 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.
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