Mechanisms of epoxyeicosatrienoic acid-induced cardioprotection

  • Author / Creator
    Chaudhary, Ketul R
  • Ischemic heart disease remains a major cause of illness, disability and death worldwide, as such there remains a need for novel pharmacological agents that protect against myocardial ischemia reperfusion (I/R) injury. Epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP) epoxygenase metabolites of arachidonic acid, which have demonstrated protective properties against cardiac I/R injury. However, the exact mechanism(s) of cardioprotection remains unknown. The work presented in this thesis investigated potential mechanisms underlying EET-induced cardioprotection in young and aged animal models. I/R injury was examine in the Langendorff isolated perfused heart model. Key results demonstrate that preventing EET-removal by inhibiting soluble epoxide hydolase (sEH), with sEH inhibitor (sEHi) or targeted deletion (sEH null), improves left ventricular functional (LVDP) recovery and reduce injury following I/R. The improved postischemic recovery was blocked by phosphoinositide 3-kinase (PI3K) inhibitors. Data demonstrated that increased B-type natriuretic peptide (BNP) mRNA and protein expression in sEH null and EET-perfused wild type (WT) hearts. Moreover, perfusion with BNP receptor antagonist attenuated the improved postischemic LVDP recovery. Increased expression of activated PKCε and Akt were found in WT hearts perfused with either 11,12-EET or BNP. In addition, treatment with the PI3K inhibitor (wortmannin) abolished improved postishcemic functional recovery in 11,12-EET treated hearts but not of BNP treated hearts. In the final study, data demonstrates that EET-induced cardioprotection remains effective in aged mice. Importantly, aging is a major risk factor for development of IHD and increases susceptibility to I/R injury. Furthermore, many cardioprotective strategies become ineffective in aged animals. Interesting data from aged mice demonstrated that the cardiomyocyte specific over-expression of CYP2J2 (CYP2J2 Tr) reduces the cardioprotective response. The loss of cardioprotection in aged CYP2J2 Tr was attributed to increased linoleic metabolite (DiHOME), oxidative stress and decreased protein phosphatase 2a activation. Moreover, all these effects and loss of cardioprotection in aged CYP2J2 Tr mice can be prevented by sEHi. In summary, results from this thesis clearly demonstrate EETs protect the heart against I/R injury and the protective effects are mediated through BNP and PI3K pathway. In addition, we demonstrate the effectiveness of EETs and sEHi in protecting the heart against I/R injury in aged animals.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • 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
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Faculty of Pharmacy and Pharmaceutical Sciences
  • Specialization
    • Pharmaceutical Sciences
  • Supervisor / co-supervisor and their department(s)
    • Seubert, John M (Pharmacy and Pharmaceutical Sciences)
  • Examining committee members and their departments
    • Dyck, Jason (Pediatric)
    • Brocks, Dion (Pharmacy and Pharmaceutical Sciences)
    • El-Kadi, Ayman (Pharmacy and Pharmaceutical Sciences)
    • Lee, Craig (Eshelman School of Pharmacy, University of North Carolina)
    • Seubert, John (Pharmacy and Pharmaceutical Sciences)
    • Jurasz, Paul (Pharmacy and Pharmaceutical Sciences)