Cytochrome P450-derived Eicosanoids, Inflammation, and Atherosclerotic Cardiovascular Disease Public Deposited

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  • March 20, 2019
Creator
  • Theken, Katherine N.
    • Affiliation: Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics
Abstract
  • Inflammation contributes to the pathogenesis of atherosclerosis from the initiation of plaque formation to progression to acute coronary syndrome clinical events. Due to the divergent effects of cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE) in the regulation of vascular tone and inflammation, alterations in the functional balance between the CYP epoxygenase and ω-hydroxylase pathways may contribute to the pathophysiology of cardiovascular disease. The objectives of the work described in this doctoral dissertation were to characterize the effect of inflammation, metabolic dysfunction, and cardiovascular disease on the functional balance between the CYP epoxygenase and ω-hydroxylase pathways, and explore the potential of modulating CYP-mediated eicosanoid metabolism as an anti-inflammatory therapeutic strategy for atherosclerotic cardiovascular disease. Acute activation of the innate immune response altered CYP-mediated eicosanoid metabolism in a tissue- and time-dependent manner. High fat diet feeding shifted the functional balance between the pathways in favor of the CYP ω-hydroxylase pathway, suggesting that dysregulation of CYP-mediated eicosanoid metabolism contributes to the pathophysiologic consequences of the metabolic syndrome. Enalapril treatment restored the functional balance between the pathways, implicating the renin-angiotensin system in mediating high fat diet-induced alterations in CYP-mediated eicosanoid metabolism. Although 20-HETE does not contribute to the acute inflammatory response to lipopolysaccharide, inhibition of the CYP ω-hydroxylase pathway may have therapeutic utility for the treatment of chronic vascular inflammation. CYP epoxygenase and ω-hydroxylase pathway function differed between healthy volunteers and patients with established atherosclerosis, and several clinical factors were associated with plasma levels of CYP-derived eicosanoids. Functional genetic variation in the CYP epoxygenase and ω-hydroxylase pathways was associated with survival in patients following an acute coronary syndrome, suggesting that therapies that specifically modulate CYP-mediated eicosanoid metabolism may represent a novel treatment strategy for atherosclerotic cardiovascular disease.
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  • In Copyright
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pharmaceutical Sciences in the Eshelman School of Pharmacy (Pharmacotherapy and Experimental Therapeutics)"
Advisor
  • Lee, Craig
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  • Chapel Hill, NC
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  • Open access
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