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The role of cytochrome P450 derived arachidonic acid metabolites against Angiotensin II-induced cardiac hypertrophy in Sprague Dawley rats and the RL-14 cell line

  • Author / Creator
    Elkhatali, Samya
  • Several cytochrome P450 (CYP) enzymes and their arachidonic acid (AA) metabolites play essential roles in the maintenance of cardiovascular health, and their alteration gives rise to a number of cardiovascular diseases, including cardiac hypertrophy and heart failure. Recent data demonstrated that 19-hydroxyeicosatetraenoic acid (19-HETE) is the major subterminal-HETE in the heart tissue and its formation is decreased during cardiac hypertrophy, while in contrast that of mid-chain HETEs increased. Therefore, our aims were; 1) to examine whether 19-HETE confers cardioprotection against angiotensin II (Ang II)-induced cardiac hypertrophy at in vitro and in vivo levels in which isoniazid (INH) was used to increase 19-HETE formation in vivo, and 2) to study the cardioprotective effect of inhibiting the formation of midchain HETEs [using 2,3',4,5'-tetramethoxystilbene (TMS)] against Ang II-induced cardiac hypertrophy also at in vitro and in vivo levels. Our results demonstrated that 19-HETE conferred a cardioprotective effect against Ang II-induced cellular hypertrophy, as indicated by the significant reduction in the β/α-MHC ratio. Echocardiographic analysis showed that INH improved heart dimensions, in addition to reversing the increase in heart weight to tibial length ratio caused by Ang II. The cardioprotective effect of INH was associated with an increased level of cardiac 19-HETE. Additionally, INH significantly reduced levels of the cardiotoxic AA metabolite 20-HETE-induced by Ang II treatment. Likewise, we demonstrated that TMS protected against Ang II-induced cardiac hypertrophy as indicated by echocardiography and heart weight to tibia length ratio. TMS significantly reduced the β/α-MHC ratio. In addition, this cardioprotective effect of TMS was associated with decreased levels of cardiac mid-chain and 20-HETE as well as significantly reducing AA levels. TMS decreased oxidative stress, inhibiting the phosphorylation of ERK1/2, p38 MAPK and the binding of p65 NF-κB. In conclusion, our results demonstrate that both INH and TMS partially protect against Ang II-induced cardiac hypertrophy through manipulating the levels of AA metabolites. This further confirms the role of CYPs, and their associated AA metabolites, in the development of cardiac hypertrophy.

  • Subjects / Keywords
  • Graduation date
    2015-11
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/R3QR4NZ78
  • 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.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Master's
  • Department
    • Faculty of Pharmacy and Pharmaceutical Sciences
  • Specialization
    • Pharmaceutical Sciences
  • Supervisor / co-supervisor and their department(s)
    • El-Kadi, Ayman (Faculty of pharmacy and pharmaceutical sciences)
  • Examining committee members and their departments
    • Baker, Glen (Department of psychiatry)
    • Brocks, Dion (Faculty of pharmacy and pharmaceutical sciences)