Translational Characterization of Arachidonic Acid Metabolism in Vascular Inflammation and Cardiovascular Disease
Public DepositedAdd to collection
You do not have access to any existing collections. You may create a new collection.
Downloadable Content
Download PDFCitation
MLA
Schuck, Robert Nathaniel. Translational Characterization of Arachidonic Acid Metabolism In Vascular Inflammation and Cardiovascular Disease. University of North Carolina at Chapel Hill, 2013. https://doi.org/10.17615/v1fp-bd79APA
Schuck, R. (2013). Translational Characterization of Arachidonic Acid Metabolism in Vascular Inflammation and Cardiovascular Disease. University of North Carolina at Chapel Hill. https://doi.org/10.17615/v1fp-bd79Chicago
Schuck, Robert Nathaniel. 2013. Translational Characterization of Arachidonic Acid Metabolism In Vascular Inflammation and Cardiovascular Disease. University of North Carolina at Chapel Hill. https://doi.org/10.17615/v1fp-bd79- Last Modified
- March 20, 2019
- Creator
-
Schuck, Robert Nathaniel
- Affiliation: Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics
- Abstract
- Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States and novel therapeutic approaches are needed to prevent its development and progression. It is well-established that inflammation is integral to the pathogenesis of coronary artery disease (CAD); therefore, inhibition of the inflammatory response has enormous therapeutic potential to prevent CAD development and progression. Cytochrome P450 (CYP) enzymes metabolize arachidonic acid to biologically active eicosanoids, and modulation of CYP-mediated arachidonic acid metabolism has emerged as a potential therapeutic target for the treatment of CAD. CYP epoxygenases from the CYP2C and CYP2J subfamilies metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs), which have potent anti-inflammatory effects, and are rapidly hydrolyzed by soluble epoxide hydrolase (sEH) to less biologically active dihydroxyeicosatrienoic acids (DHETs). In contrast, CYP ω-hydroxylase enzymes from the CYP4F and CYP4A subfamilies catalyze the conversion of arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE) which exhibits potent pro-inflammatory effects. Accumulating evidence indicates that CYP-derived eicosanoids are key regulators of inflammation and endothelial function; however, the functional association between CYP-mediated eicosanoid metabolism, inflammation and endothelial dysfunction, and CAD remains poorly understood. Therefore, the aim of this dissertation is to characterize the functional contribution of CYP-mediated eicosanoid metabolism to the regulation of systemic and vascular inflammation within the clinical context of CAD. Using an integrated combination of systems wide and candidate pathway approaches in humans, and pharmacologic and genetic approaches in mice, our findings demonstrate that genes regulating the inflammatory response associate with the presence and severity of CAD. Moreover, we identified a subset of stable CAD patients with enhanced CYP ω-hydroxylase and sEH metabolic function who had advanced endothelial dysfunction and vascular inflammation. In addition, our preclinical studies demonstrated that fatty liver disease-associated inflammation suppressed hepatic CYP epoxygenase activity, and genetic disruption of sEH restored EET levels, and attenuated hepatic and systemic inflammation. Collectively, this dissertation demonstrates that targeted therapeutic strategies that modulate CYP-mediated arachidonic acid metabolism represent a rational anti-inflammatory approach for the treatment of CAD, and thus lays a critical foundation for future studies that directly evaluate the therapeutic effects of modulating CYP-mediated eicosanoid metabolism in CAD patients.
- Date of publication
- 2013
- Keyword
- DOI
- Resource type
- Rights statement
- In Copyright
- Advisor
- Lee, Craig
- Degree
- Doctor of Philosophy
- Graduation year
- 2013
- Language
- Publisher
Relations
- Parents:
This work has no parents.
Items
Thumbnail | Title | Date Uploaded | Visibility | Actions |
---|---|---|---|---|
Schuck_unc_0153D_13906.pdf | 2019-04-12 | Public | Download |