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Cardioprotective Effects of Soluble Epoxide Hydrolase Inhibition Following Myocardial Infarction
- Author / Creator
- Jamieson, Kristi Lockhart
Ischemic heart disease (IHD) is a significant cause of morbidity and mortality for Canadians. While mortality rates from myocardial infarction (MI) and heart failure (HF) have decreased, IHD remains the number one cause of premature mortality. Both age and sex are important contributors for IHD risk. Aging promotes pathophysiological changes over time that reduce the ability of the heart to adequately respond to stress. Importantly, there are differences in cardiac aging between the sexes. CYP450 metabolism of N-3 and N- 6 polyunsaturated fatty acids (PUFAs) generates numerous metabolites, oxylipids, that exhibit a wide range of cellular effects. Previous studies demonstrate oxylipids can regulate and protect mitochondria resulting in preserved cardiac function following ischemic injury. Oxylipids are further metabolised by soluble epoxide hydrolase (sEH) into corresponding diol products with numerous activities. The work presented in this dissertation investigated the effects of inhibiting sEH in aged mice. Moreover, we analyse human myocardial samples from male and female explanted hearts to characterize oxylipid metabolism and mitochondrial function in non-failing control (NFC) and ischemic cardiomyopathy (ICM) patients.
MI was induced in young and aged mice using permanent occlusion of the left anterior descending coronary artery (LAD). Human tissues were obtained from male and female patients with MI (ICM) as part of the Human Explanted Heart Program (HELP) and NFC cardiac tissues were obtained from the Human Organ Procurement and Exchange (HOPE) program at the University of Alberta. Key results suggest mice with genetic deletion or oral treatment with sEH inhibitor tAUCB exhibit significantly preserved cardiac function and increased survivability following MI. These results were associated with conserved mitochondrial function. Importantly, these cardioprotective effects were blunted over age and were more robust in females. In human myocardial samples, individuals with a previous MI had significantly elevated levels of sEH expression correlating with changes to the PUFA metabolite profile and decreases in mitochondrial function.
In summary, the data presented in this thesis suggest targeting sEH in aged mice effectively reduces ischemic injury through preserving mitochondrial function. Unexpectedly, data from our aged mouse model indicate an age-dependent sex-difference, suggesting targeting sEH may be more effective in improving post-ischemic heart function in aged females. Moreover, data from human explanted hearts suggest sEH may be a potential pharmacological target for humans with ischemic cardiomyopathy.
- Graduation date
- Fall 2020
- Type of Item
- Doctor of Philosophy
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