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THE ROLE OF CYTOCHROME P450 AND THEIR ASSOCIATED ARACHIDONIC ACID METABOLITES IN THE INITIATION AND PROGRESSION OF CARDIAC HYPERTROPHY Open Access

Descriptions

Other title
Subject/Keyword
Cytochrome P450
cardiac hypertrophy
Soluble epoxide hydrolase
Epoxyeicosatrienoic acids
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Althurwi, Hassan N
Supervisor and department
El-Kadi, Ayman (Faculty of Pharmacy and Pharmaceutical Sciences)
Examining committee member and department
Anderson, Hope (Faculty of Pharmacy & Department of Pharmacology & Therapeutics, University of Manitoba)
Marsh, Sharon (Faculty of Pharmacy and Pharmaceutical Sciences)
Baker, Glen (Department of Psychiatry)
Brocks, Dion (Faculty of Pharmacy and Pharmaceutical Sciences)
Jurasz, Paul (Faculty of Pharmacy and Pharmaceutical Sciences)
Department
Faculty of Pharmacy and Pharmaceutical Sciences
Specialization
PHARMACEUTICAL SCIENCES
Date accepted
2015-12-15T15:18:27Z
Graduation date
2016-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Heart failure (HF) is the leading cause of mortality and disability in adults worldwide. Cardiac hypertrophy is an independent risk factor and one of the major hallmarks of HF. Research in cardiac hypertrophy is considered as a research into the early events in the development of HF. The expression of cytochrome P450 (CYP) and soluble epoxide hydrolase (sEH) enzymes has been identified in the heart and their levels have been reported to be altered during cardiac hypertrophy and HF. The role of CYP enzymes in cardiac hypertrophy emerge from their ability to metabolize arachidonic acid to the cardioprotective epoxyeicosatrienoic acids (EETs) and the cardiotoxic 20-hydroxyeicosatetraenoic acid (20-HETE) metabolites. Therefore, the objective of the present work was to investigate the role of CYP enzymes, sEH, and CYP-derived arachidonic acid metabolites in the pathogenesis of cardiac hypertrophy. Our results show that cardiac hypertrophy was initiated after 72 hours and 6 hours of isoproterenol treatment in rat and human fetal ventricular cell line, RL-14, respectively. Studies performed at the prehypertrophy phase showed decreases in the expression of CYP epoxygenases and an induction of sEH activity. Consequently, lower EET and higher dihydroxyeicosatrienoic acid (DHETs) levels were observed prior to cardiac enlargement. On the other hand, isoproterenol caused an induction of CYP1A1, CYP1B1, CYP2B1, CYP2B2, CYP4A3 and CYP4F4 expression during the established phase of cardiac hypertrophy, which consequently led to lower levels of EETs and higher levels of 20-HETE. Interestingly, inhibition of sEH by 1-(1-methanesulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPS) attenuated the progression of cardiac hypertrophy and fibrosis induced by isoproterenol. Moreover, TUPS significantly inhibited the isoproterenol-mediated effects on CYP enzymes and their associated metabolites. Furthermore, we showed that fenofibrate significantly induced the cardiac expression of CYP epoxygenases such as CYP2B1, CYP2B2, CYP2C11, and CYP2C23, whereas it decreased the expression of the cardiac ω-hydroxylase CYP4A3. Consequently, fenofibrate significantly increased the formation of cardiac EETs whereas it decreased the cardiac level of 20-HETE. Interestingly, fenofibrate significantly decreased the hypertrophic markers and the increase in heart-to-body weight ratio induced by isoproterenol. Finally, we showed that increasing EET levels by induction of CYP epoxygenases, sEH inhibition, or exogenous administration of EET prevented the initiation of cardiac hypertrophy through a nuclear factor-kB-mediated mechanism. Taken together, these findings reveal a crucial role of CYP, sEH, and CYP-mediated arachidonic acid metabolism in the initiation and progression of cardiac hypertrophy, which may lead to discovery of novel targets for the prevention of HF at an early stage.
Language
English
DOI
doi:10.7939/R3QB9VB21
Rights
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
Althurwi, H. N., Z. H. Maayah, O. H. Elshenawy and A. O. El-Kadi (2015). "Early Changes in Cytochrome P450s and Their Associated Arachidonic Acid Metabolites Play a Crucial Role in the Initiation of Cardiac Hypertrophy Induced by Isoproterenol." Drug Metab Dispos 43(8): 1254-1266.Althurwi, H. N., O. H. Elshenawy and A. O. El-Kadi (2014). "Fenofibrate modulates cytochrome P450 and arachidonic acid metabolism in the heart and protects against isoproterenol-induced cardiac hypertrophy." J Cardiovasc Pharmacol 63(2): 167-177.Althurwi, H. N., M. M. Tse, G. Abdelhamid, B. N. Zordoky, B. D. Hammock and A. O. El-Kadi (2013). "Soluble epoxide hydrolase inhibitor, TUPS, protects against isoprenaline-induced cardiac hypertrophy." Br J Pharmacol 168(8): 1794-1807.

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