TRANSLATIONAL APPROACHES TO UNDERSTANDING THE ROLE OF CYTOCHROME P450-DERIVED EPOXYEICOSATRIENOIC ACIDS IN CORONARY ARTERY DISEASE

Oni-Orisan, Akinyemi

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March 19, 2019

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Oni-Orisan, Akinyemi
- Affiliation: Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics

Abstract

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in the United States (US). Most notably, coronary artery disease (CAD) including its clinical complications (acute myocardial infarction [AMI] and heart failure) is the primary source of this public health burden. This burden highlights the need for new therapies that target biological pathways integral to the pathophysiology of CAD and its consequences. However, a more thorough understanding of the mechanisms underlying the pathophysiology is necessary to facilitate the development of new therapeutic strategies. Epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP)-derived metabolites of arachidonic acid that are hydrolyzed by soluble epoxide hydrolase (sEH) into the less biologically active dihydroxyeicosatrienoic acids (DHETs). EETs yield potent cardiovascular protective effects in preclinical models of atherosclerosis, ischemia reperfusion (IR) injury, and post-AMI ventricular remodeling, suggesting that increasing EET levels may be a viable therapeutic strategy for CAD, AMI, and post-AMI maladaptive ventricular remodeling. Key questions, however, remain to be addressed prior to translation of therapeutic EET-promoting strategies into successful clinical trials. The overall aim of this dissertation is to advance our understanding of the role of the EET metabolic pathway across the full spectrum of CAD and post-AMI consequences as a means to determine the biological and therapeutic importance of EETs in the progression of this disease cascade. We used both pre-clinical and human studies to complete the specific aims of this work. We found that obstructive CAD is significantly and independently associated with lower circulating EET levels. In addition, we observed that a functionally relevant polymorphism linked with enhanced EET hydrolysis was potentially associated with mortality in a population of AMI patients. Moreover, we showed that mice with cardiomyocyte-specific overexpression of human sEH exhibited enhanced IR-induced myocardial collagen deposition. Overall, we demonstrated that the EET metabolic pathway may play a role in the pathophysiology of CAD and its associated complications including the development of coronary atherosclerosis, post-AMI early ventricular remodeling, and post-AMI mortality. These findings set the stage for future studies that investigate the therapeutic utility of modulating EETs in CAD patients.

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