Cardioprotective effects of n-3 and n-6 PUFA derived epoxylipids against age-related cardiac alterations

  • Author / Creator
    Hedieh Keshavarz-Bahaghighat
  • Age-associated changes leading to a decline in cardiac structure and function contribute to the increased susceptibility and incidence of cardiovascular diseases (CVD) in elderly individuals. A steady decline in mitochondrial function is recognized as an important biological consequence found in the aging heart which contributes to increased cellular stress and age-related CVD pathogenesis. There is growing evidence indicating CYP450 epoxygenase-mediated metabolites of n-3 and n-6 polyunsaturated fatty acids are active lipid mediators regulating cardiac homeostasis. These epoxy metabolites are rapidly hydrolyzed and inactivated by the soluble epoxide hydrolase (sEH). Both genetic deletion and pharmacological inhibition of sEH has been demonstrated to mediate cardioprotective, anti-inflammatory and anti-hypertensive responses, as well limit mitochondrial injury. In this thesis, we characterized cardiac differences in young and aged sEH null mice compared to the corresponding wild-type (WT) mice. Significant increased cardiac hypertrophy was observed in all aged groups except female sEH null mice. Sirtuin-3 (Sirt-3) activity significantly decreased over aging in WT both males and females associated with increased expression level of acetyl manganese superoxide dismutase (acetyl Mn-SOD). Genetic deletion of sEH preserved Sirt-3 activity coupled with lower level of acetyl Mn-SOD in the hearts of both female and male mice. Consistent with these changes, the activity level of SOD significantly decreased in WT animals but was preserved in aged sEH null animals. There was an age-related disruption in mitochondrial ultrastructure in WT animals which was attenuated is sEH null mice. Together these data demonstrate the sexual dimorphic pattern in beneficial effects of genetic deletion of sEH in limiting age-related cardiac alterations.

  • Subjects / Keywords
  • Graduation date
    Spring 2021
  • Type of Item
  • Degree
    Master of Science
  • 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.