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Role of Cytochrome P450 Enzymes in Inflammation-induced Cardiac Hypertrophy
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- Author / Creator
- ElKhatib, Mohammed
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Heart failure (HF) is typically preceded by cardiac hypertrophy (CH), which is characterized by cardiomyocytic enlargement following stress. During CH development, expression of cytochrome P450 enzymes (CYPs) and metabolism of arachidonic acid (AA) are altered. Cardiac CYPs metabolize AA into multiple biologically active eicosanoids, that are classified into hydroxyeicosatetraenoic acids (HETEs) and epoxyeicosatrienoic acids (EETs). HETEs are further classified as terminal, subterminal, and mid-chain HETEs. Mid-chain HETEs are a distinct group of CYP1B1-derived eicosanoids that show cardiotoxic hypertrophic properties. Inflammation is involved in CH pathophysiology, but mechanisms of inflammation-induced CH and alteration of CYP-mediated AA metabolism remain elusive. Comprehending the mechanisms of inflammation-induced CH would be invaluable in identifying the molecular entities that should be targeted for pharmacological interventions. Therefore, the objectives of the present work were to investigate the impacts of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and lipopolysaccharide (LPS) on the development of cellular hypertrophy (CeH), expression of CYP1B1, and CYP1B1-mediated AA metabolism, as well as the role of CYP1B1 in TNF-α, IL-6, and LPS -induced CeH in vitro. Our results show that TNF-α, IL-6, and LPS induce mRNA expression of hypertrophic markers, significantly increase cell surface area, induce CYP1B1 at mRNA, protein, and activity levels, and enantioselectively modulate CYP-mediated AA metabolism in favor of cardiotoxic mid-chain HETEs. These effects are ameliorated in the presence of CYP1B1-siRNA or trans-resveratrol. In conclusion, our results demonstrate the crucial role of CYP1B1 in TNF-α, IL-6, and LPS -induced CeH and highlight CYP1B1 as a clear target for potential therapeutic interventions for the prevention and treatment of CeH.
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- Subjects / Keywords
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- Graduation date
- Spring 2024
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- Type of Item
- Thesis
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- Degree
- Master of Science
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- License
- This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. 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.