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The role of cytochrome P450 1B1 and its associated metabolites in the pathogenesis of cardiac hypertrophy and drug-induced heart failure
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- Author / Creator
- Alma'ayah, Zaid H
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Heart failure (HF) is one of the most widespread and lethal forms of heart disease worldwide. Most HF patients have a history of hypertension and left ventricular hypertrophy in addition to drug-induced cardiotoxicity. Mechanisms regulating cardiac hypertrophy and drug-induced HF have been the focus of intense investigation in recent years. Among these mechanisms, cytochrome P450 (CYP) enzymes have been shown to play an important role in the regression or the progression of cardiac hypertrophy through the oxidation of arachidonic acid (AA) into cardioprotective epoxyeicosatrienoic acid (EETs) and cardiotoxic hydroxyeicosatetraenoic acids (HETEs). Of particular interest, numerous experimental studies have demonstrated a role for CYP1B1 and its associated mid-chain hydroxyeicosatetraenoic acids (mid-chain HETEs) metabolite in the development of cardiovascular diseases. Therefore, the objective of the present work was to investigate the role of CYP1B1 and its associated metabolites in the pathogenesis of cardiac hypertrophy and doxorubicin (DOX)-induced cardiotoxicity. Our results demonstrated that CYP1B1 AA metabolites, mid-chain HETEs, induced cellular hypertrophy in the human cardiomyocytes RL-14 cell line as evidenced by the induction of cardiac hypertrophic markers in addition to the increase in cell surface area. Moreover, mid-chain HETEs were able to induce cellular hypertrophy through MAPK- and NF-κB-dependent mechanisms. Interestingly, inhibition of CYP1B1 and its associated mid-chain HETE metabolites using 2,3',4,5'-tetramethoxystilbene (TMS), a selective CYP1B1 inhibitor, protected against DOX-induced cardiotoxicity and isoproterenol (ISO)-induced cardiac hypertrophy. Mechanistically, the protective effect of TMS was mediated through the inhibition of MAPK and NF-κB signaling pathways. Of interest, overexpression of CYP1B1 significantly induced cellular hypertrophy and mid-chain HETE metabolites. In contrast to the negative effects of the cardiotoxic metabolites generated by CYP1B1, CYP1B1 also has an important role in the formation of a cardioprotective metabolite, 2-methoxyestradiol, 2ME. Therefore, we have investigated whether 2ME would prevent cardiac hypertrophy induced by abdominal aortic constriction (AAC). Our results showed that 2ME significantly inhibited AAC-induced left ventricular hypertrophy. The antihypertrophic effect of 2ME was associated with a significant inhibition of CYP1B1 and its associated mid-chain HETE metabolites. Based on proteomics data, the protective effect of 2ME is linked to the induction of antioxidant and anti-inflammatory proteins in addition to the modulation of proteins involved in myocardial energy metabolism. In vitro, 2ME has shown a direct antihypertrophic effect through the modulation of MAPK and NF-κB signaling pathways. In conclusion, our findings may shed light on the role of CYP1B1 in the development of cardiac hypertrophy and indicate that CYP1B1 can serve as a novel target for the treatment of heart diseases. Such observations will raise the potential of having selective inhibitors of this enzyme, such as 2ME and TMS, to be used clinically in the treatment of cardiovascular diseases.
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- Graduation date
- Fall 2018
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- Type of Item
- Thesis
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- Degree
- Doctor of Philosophy
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- License
- 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.