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Profile of John M Seubert, PhD

John M Seubert
Assistant Professor
Faculty of Pharmacy & Pharmaceutical Sciences
4130 Dentistry/Pharmacy Centre
University of Alberta
Edmonton AB  T6G 2N8

Tel: 780.492.0007
Fax: 780.492.1217


  • BSc, Aquatic Toxicology, Simon Fraser University
  • MSc, Aquatic Toxicology, Simon Fraser University
  • PhD, Pharmacology & Toxicology, University of Western Ontario
  • Postdoctoral Fellowship (Cardiovascular Pharmacology), National Institutes of Environmental Health Sciences (NIEHS/NIH)


Acute myocardial infarction (AMI) continues to be the leading cause of death in Canada. Myocardial infarction occurs when ischemia exceeds a critical threshold and overwhelms cellular repair mechanisms resulting in irreversible myocardial cell damage or death. This is the primary factor in the pathogenesis of ischemic/reperfusion injury and myocyte loss associated with cardiovascular disease (CVD). Targeting strategies that limit the damage has been a major focus of research. Despite substantial research in cardioprotective mechanisms, the increasing incidence and prevalence of heart failure after AMI highlight the need for a better understanding of the pathophysiological mechanisms.

Arachidonic acid (AA), a polyunsaturated fatty acid normally found esterified to cell membrane glycerophospholipids, can be released by phospholipases in response to several stimuli such as ischemia. Cytochrome P450 epoxygenases metabolize AA to epoxyeicosatrienoic acids (EETs) which are converted to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (Ephx2, sEH). CYP-derived metabolites of arachidonic acid play critical roles in modulating fundamental biologic processes. The EETs are lipid mediators which act as potent cellular signaling molecules both in cardiac and extracardiac tissue. Environmental or genetic factors that alter P450 expression and/or function lead to changes in production of bioactive eicosanoids. Such effects can influence cell and organ function in either an adverse or beneficial manner. CYP isozymes expressed in the heart, notably CYP2J2, generate EETs which we have been shown to be cardioprotective. In contrast, other CYP isozymes (CYP2C and CYP4A) generate products which are thought to be detrimental to the heart, such as ROS and 20-HETE. Traditionally, investigation into the role of CYP isozymes has generally focused on hepatic and renal drug metabolism and function. There is little known about the importance of this endogenous system within the heart. Even though, the heart contains significant levels of functionally active CYP. Interestingly, recent human epidemiological evidence has identified a correlation between CYP2J2 polymorphisms and coronary artery disease, as well as EPHX2 and coronary heart disease. These studies highlight the clinical relevance and importance of this arachidonic acid metabolism pathway to cardiac function and protection.

The central focus of our research is to investigate the role of EETs in myocardial function and protection against ischemic injury. In order to investigate the cardioprotective role of EETs, genetically modified mouse models are utilized. These mice were designed to elevate intracellular EET levels; either by increasing production, transgenic mice overexpressing CYP2J2, or slowing removal, mice with the targeted deletion of sEH. Various complementary approaches ranging from gene expression patterns and primary cell culture experiments to tissue physiology are utilized to understand the cellular mechanisms of EET-mediated cardioprotection. This will help elucidate the arachidonic acid pathway as a novel therapeutic target for the treatment of cardiovascular diseases.

This research is supported by the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada and Alberta.

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