Cytochrome P450 Derived Eicosanoids and Inflammation

Summary

Principal Investigator: Craig R Lee
Abstract: ABSTRACT: Inflammation is a fundamental process which plays an integral role in the pathogenesis of numerous disease states in humans. Nuclear factor kappa B (NF-[unreadable]B) is a central mediator of the inflammatory response via transcriptional activation of cytokine, chemokine and cellular adhesion molecule expression. Consequently, identification of novel strategies aimed at inhibition of this pathological process offers substantial therapeutic potential. Arachidonic acid is oxidatively metabolized by cytochrome P450 (CYP) epoxygenases from the CYP2J and CYP2C subfamilies to epoxyeicosatrienoic acids (EETs) in hepatic and extra-hepatic tissue. The EETs are rapidly hydrolyzed by soluble epoxide hydrolase (sEH) to less active dihydroxyeicosatrienoic acids (DHETs). Arachidonic acid is also metabolized to 20-hydroxyeicosatetraenoic acid (20-HETE) by CYP [unreadable]- hydroxylases from the CYP4A and CYP4F subfamilies. Recent evidence has demonstrated that CYP-derived EETs and 20-HETE possess anti- and pro-inflammatory effects, respectively. However, the contribution of CYP-mediated eicosanoid metabolism to the regulation of inflammation in vivo has not been rigorously characterized. We hypothesize that the functional balance between CYP epoxygenase- and CYP [unreadable]- hydroxylase-mediated arachidonic acid metabolism is integral to the regulation of NF-[unreadable]B-mediated inflammatory responses in vivo, and modulation of this balance in favor of the CYP epoxygenase pathway offers substantial therapeutic potential. The primary objectives of this proposal are to: (1) define the impact of the inflammatory response on hepatic and extra-hepatic CYP-mediated eicosanoid metabolism, (2) define the functional role of CYP epoxygenase-mediated EET biosynthesis and sEH-mediated EET hydrolysis in the regulation of inflammation, and (3) characterize the relative impact of CYP epoxygenase and CYP [unreadable]- hydroxylase pathway modulation on inflammatory responses in vivo. This project will utilize novel transgenic and knock-out mice and pharmacological tools to manipulate CYP-mediated eicosanoid metabolism in vivo, while characterizing NF-[unreadable]B-mediated inflammatory responses using established molecular biology and analytical techniques. Collectively, this series of novel experiments will define the mechanistic contribution of CYP epoxygenase-derived EETs and CYP [unreadable]-hydroxylase-derived 20-HETE to the regulation of hepatic and extra-hepatic inflammatory responses in vivo, and facilitate the development of new anti-inflammatory strategies with potential therapeutic application to numerous disease states in humans.
Funding Period: 2009-08-01 - 2015-05-31
more information: NIH RePORT

Top Publications

  1. pmc Cytochrome P450 epoxygenases, soluble epoxide hydrolase, and the regulation of cardiovascular inflammation
    Yangmei Deng
    Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599 7569, USA
    J Mol Cell Cardiol 48:331-41. 2010
  2. pmc Vascular characterization of mice with endothelial expression of cytochrome P450 4F2
    Jennifer Cheng
    Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA
    FASEB J 28:2915-31. 2014
  3. pmc Epoxyeicosanoids promote organ and tissue regeneration
    Dipak Panigrahy
    Vascular Biology Program and Department of Surgery, Boston Children s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 110:13528-33. 2013
  4. pmc Role of endothelial soluble epoxide hydrolase in cerebrovascular function and ischemic injury
    Wenri Zhang
    Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, Oregon, United States of America
    PLoS ONE 8:e61244. 2013
  5. pmc Cytochrome P450 2J2 is protective against global cerebral ischemia in transgenic mice
    Rui Li
    Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People s Republic of China
    Prostaglandins Other Lipid Mediat 99:68-78. 2012
  6. pmc Dual modulation of cyclooxygenase and CYP epoxygenase metabolism and acute vascular inflammation in mice
    Akinyemi Oni-Orisan
    Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
    Prostaglandins Other Lipid Mediat 104:67-73. 2013
  7. pmc Enalapril reverses high-fat diet-induced alterations in cytochrome P450-mediated eicosanoid metabolism
    Katherine N Theken
    Div of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, Univ of North Carolina, Chapel Hill, NC 27599, USA
    Am J Physiol Endocrinol Metab 302:E500-9. 2012
  8. pmc Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice
    Dipak Panigrahy
    Vascular Biology Program, Children s Hospital Boston, Boston, Massachusetts, USA
    J Clin Invest 122:178-91. 2012
  9. pmc Endothelial expression of human cytochrome P450 epoxygenase CYP2C8 increases susceptibility to ischemia-reperfusion injury in isolated mouse heart
    Matthew L Edin
    Division of Intramural Research, National Institute for Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA
    FASEB J 25:3436-47. 2011
  10. pmc Endothelial CYP epoxygenase overexpression and soluble epoxide hydrolase disruption attenuate acute vascular inflammatory responses in mice
    Yangmei Deng
    Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, NC 27599 7569, USA
    FASEB J 25:703-13. 2011

Detail Information

Publications13

  1. pmc Cytochrome P450 epoxygenases, soluble epoxide hydrolase, and the regulation of cardiovascular inflammation
    Yangmei Deng
    Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599 7569, USA
    J Mol Cell Cardiol 48:331-41. 2010
    ....
  2. pmc Vascular characterization of mice with endothelial expression of cytochrome P450 4F2
    Jennifer Cheng
    Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA
    FASEB J 28:2915-31. 2014
    ..M., Lih, F. B., Garcia, V., Shaik, J. S. B., Tomer, K. B., Flake, G. P., Falck, J. R., Lee, C. R., Poloyac, S. M., Schwartzman, M. L., Zeldin, D. C. Vascular characterization of mice with endothelial expression of cytochrome P450 4F2...
  3. pmc Epoxyeicosanoids promote organ and tissue regeneration
    Dipak Panigrahy
    Vascular Biology Program and Department of Surgery, Boston Children s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 110:13528-33. 2013
    ..Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis. ..
  4. pmc Role of endothelial soluble epoxide hydrolase in cerebrovascular function and ischemic injury
    Wenri Zhang
    Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, Oregon, United States of America
    PLoS ONE 8:e61244. 2013
    ....
  5. pmc Cytochrome P450 2J2 is protective against global cerebral ischemia in transgenic mice
    Rui Li
    Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People s Republic of China
    Prostaglandins Other Lipid Mediat 99:68-78. 2012
    ..These results indicate that CYP2J2 overexpression exerts marked neuroprotective effects against ischemic injury by a mechanism linked to increased level of circulating EETs and increases CBF and reduction of apoptosis...
  6. pmc Dual modulation of cyclooxygenase and CYP epoxygenase metabolism and acute vascular inflammation in mice
    Akinyemi Oni-Orisan
    Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
    Prostaglandins Other Lipid Mediat 104:67-73. 2013
    ....
  7. pmc Enalapril reverses high-fat diet-induced alterations in cytochrome P450-mediated eicosanoid metabolism
    Katherine N Theken
    Div of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, Univ of North Carolina, Chapel Hill, NC 27599, USA
    Am J Physiol Endocrinol Metab 302:E500-9. 2012
    ..Future studies delineating the underlying mechanisms and evaluating the therapeutic potential of modulating CYP-derived EETs and 20-HETE in metabolic diseases are warranted...
  8. pmc Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice
    Dipak Panigrahy
    Vascular Biology Program, Children s Hospital Boston, Boston, Massachusetts, USA
    J Clin Invest 122:178-91. 2012
    ..Thus, our data indicate a central role for EETs in tumorigenesis, offering a mechanistic link between lipid signaling and cancer and emphasizing the critical importance of considering possible effects of EET-modulating drugs on cancer...
  9. pmc Endothelial expression of human cytochrome P450 epoxygenase CYP2C8 increases susceptibility to ischemia-reperfusion injury in isolated mouse heart
    Matthew L Edin
    Division of Intramural Research, National Institute for Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA
    FASEB J 25:3436-47. 2011
    ..These data demonstrate that increased ROS generation and enhanced DiHOME synthesis by endothelial CYP2C8 impair functional recovery and mask the beneficial effects of increased EET production following I/R...
  10. pmc Endothelial CYP epoxygenase overexpression and soluble epoxide hydrolase disruption attenuate acute vascular inflammatory responses in mice
    Yangmei Deng
    Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, NC 27599 7569, USA
    FASEB J 25:703-13. 2011
    ....
  11. pmc Activation of the acute inflammatory response alters cytochrome P450 expression and eicosanoid metabolism
    Katherine N Theken
    Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA
    Drug Metab Dispos 39:22-9. 2011
    ..Further study is necessary to determine whether therapeutic restoration of the functional balance between the P450 epoxygenase and ω-hydroxylase pathways is an effective anti-inflammatory strategy...
  12. pmc Endothelial expression of human cytochrome P450 epoxygenases lowers blood pressure and attenuates hypertension-induced renal injury in mice
    Craig R Lee
    Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA
    FASEB J 24:3770-81. 2010
    ..We conclude that endothelial CYP epoxygenase function contributes to the regulation of blood pressure...
  13. ncbi Epoxyeicosatrienoic acids and cardioprotection: the road to translation
    Akinyemi Oni-Orisan
    Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
    J Mol Cell Cardiol 74:199-208. 2014
    ....

Research Grants31

  1. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  2. AMPK Endothelial Cell Dysfunction and the Metabolic Syndrome (PROGRAM PROJECT)
    Neil B Ruderman; Fiscal Year: 2013
    ..The proposed studies should both yield novel insights into the biological bases for the premature atherosclerosis and impaired angiogenesis associated with this entity and suggest new therapeutic targets for their prevention...
  3. Ether Lipids, Elcosanoids, and Lung Cell Pathophysiology
    CHRISTINA CARROLL LESLIE; Fiscal Year: 2013
    ..By using multidisciplinary approaches, we will determine the structural identity of lipid mediators, the molecular mechanisms involved in their production and how they function to regulate lung responses. ..
  4. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..abstract_text> ..
  5. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  6. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
    ..abstract_text> ..
  7. Coordinating Center of Excellence in Social Promotion of Health Equity Research
    GLORIA S MCCUTCHEON; Fiscal Year: 2013
    ..abstract_text> ..
  8. Mechanisms and Interventions for Methamphetamine and HIV-1 Induced CNS Injury
    Yuri Persidsky; Fiscal Year: 2013
    ..abstract_text> ..
  9. Structural bases of the functions of RNA-protein machines
    THOMAS ARTHUR STEITZ; Fiscal Year: 2013
    ..Also of interest will be the ways in which the structures and properties of RNA molecules can be utilized to carry out various biological functions often analogous to those performed by proteins. ..
  10. EICOSANOIDS AND VASCULAR WALL REMODELING
    Gadiparthi N Rao; Fiscal Year: 2013
    ..Such knowledge would be useful in the development of therapeutic drugs against vascular diseases such as atherosclerosis. ..
  11. Mechanisms of Microvascular Control and Coordination in Health and Disease
    Gerald A Meininger; Fiscal Year: 2013
    ..End of Abstract) ..
  12. Functional Annotation of the Pancreatic Cancer Genome
    Steven D Leach; Fiscal Year: 2013
    ..Together, these studies will dramatically accelerate the functional annotation of the pancreatic cancer genome, setting the stage for future therapeutic applications. ..
  13. INTEGRATED MECHANISMS OF CARDIAC MALADAPTATION
    R John Solaro; Fiscal Year: 2013
    ..Studies proposed here offer the potential for novel diagnostic procedures early in the progression of the disorders, and targets for novel therapies. (End of Abstract) ..
  14. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..