Cytochromes P450 metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs) which have potent effects on cardiovascular and renal function. EETs are metabolized to corresponding diols (DHETs) by soluble epoxide hydrolase (sEH). Current research involves: (1) characterization of CYP2J and CYP2C subfamily P450s at the biochemical and molecular levels;(2) evaluation of the functional roles of CYP2J products in cardiovascular and renal physiology;and (3) examination of this pathway in selected animal models of human disease (ischemic heart disease, hypertension, atherosclerosis, cancer). We have discovered a number of mammalian CYP2Js, although we have focused most of our efforts on human CYP2J2 and mouse CYP2J5. Human CYP2J2 is the major human P450 expressed in heart and vasculature, where it is localized to cardiac myocytes and endothelial cells, and is active in the metabolism of AA to EETs. CYP2J2-derived EETs are vasodilators, inhibit cytokine-induced endothelial cell adhesion molecule expression, induce tissue plasminogen activator gene expression, inhibit vascular smooth muscle cell migration, protect endothelial cells against hypoxia-reoxygenation injury and apoptosis, upregulate endothelial nitric oxide biosynthesis, affect cardiac electrophysiology, and protect the heart from ischemic injury. CYP2J2 transgenic mice (alpha-myosin heavy chain promoter driven cardiac-specific expression) were developed to study the effects of increased EETs on cardiac function in vivo. These mice have normal basal heart anatomy and function, improved post-ischemic left ventricular function, shortened cardiac action potential, altered cardiac electrophysiology, and enhanced beta-adrenergic receptor responsiveness. Similarly, sEH null mice which exhibit reduced EET hydrolysis have improved postischemic functional recovery. We have also developed transgenic mice in which CYP2J2, CYP2C8 or sEH are expressed exclusively in endothelial cells (Tie2 promoter driven) to examine the role of these enzymes and their products on vascular function. The phenotype of these mice is currently being evaluated. The human CYP2J2 gene has been cloned, sequenced and characterized. We have identified several functionally relevant CYP2J2 polymorphic variants, one of which is associated with reduced CYP2J2 expression and is associated with risk of cardiovascular disease in several cohorts. We have also identified functionally relevant polymorphisms in the sEH gene and have shown that they are associated with cardiovascular disease risk in a large multiethnic cohort in the U.S. CYP2J5 is a major murine P450 arachidonic acid epoxygenase expressed in the kidney and localized to proximal tubules. To evaluate the role of this P450 and its eicosanoid products in renal function and blood pressure regulation, we disrupted the Cyp2j5 gene by homologous recombination. CYP2J5 null mice have spontaneous hypertension that persists on both high and low salt diets. The hypertension is much more severe in females, is associated with reduced circulating estradiol levels, and is responsive to estrogen supplementation. CYP2J5 null female mice also have increased proximal tubular transport rates, enhanced vascular responsiveness to angiotensin II and endothelin, and reduced fertility compared to wild type counterparts. This new animal model will lead to a better understanding of the complex interrelationship between renal P450s, sex hormones, renal eicosanoids and blood pressure regulation. Consistent with these findings, we have shown that there is an association between CYP2J2 polymorphic variants and hypertension in a cohort from Tennessee.

Project Start
Project End
Budget Start
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Support Year
18
Fiscal Year
2012
Total Cost
$1,321,144
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Hoopes, Samantha L; Gruzdev, Artiom; Edin, Matthew L et al. (2017) Generation and characterization of epoxide hydrolase 3 (EPHX3)-deficient mice. PLoS One 12:e0175348
Jerschow, Elina; Edin, Matthew L; Pelletier, Teresa et al. (2017) Plasma 15-Hydroxyeicosatetraenoic Acid Predicts Treatment Outcomes in Aspirin-Exacerbated Respiratory Disease. J Allergy Clin Immunol Pract 5:998-1007.e2
Hanif, Ahmad; Edin, Matthew L; Zeldin, Darryl C et al. (2017) Vascular Endothelial Over-Expression of Human Soluble Epoxide Hydrolase (Tie2-sEH Tr) Attenuates Coronary Reactive Hyperemia in Mice: Role of Oxylipins and ?-Hydroxylases. PLoS One 12:e0169584
Hanif, Ahmad; Edin, Matthew L; Zeldin, Darryl C et al. (2017) Reduced coronary reactive hyperemia in mice was reversed by the soluble epoxide hydrolase inhibitor (t-AUCB): Role of adenosine A2A receptor and plasma oxylipins. Prostaglandins Other Lipid Mediat 131:83-95
Hanif, Ahmad; Edin, Matthew L; Zeldin, Darryl C et al. (2017) Vascular endothelial overexpression of human CYP2J2 (Tie2-CYP2J2 Tr) modulates cardiac oxylipin profiles and enhances coronary reactive hyperemia in mice. PLoS One 12:e0174137
Hu, Jiong; Geyer, Alexandra; Dziumbla, Sarah et al. (2017) Prostaglandins and Other Lipid Mediators (POLM), Special Issue of the 6th European workshop on lipid mediators: Role of Müller cell cytochrome P450 2c44 in murine retinal angiogenesis. Prostaglandins Other Lipid Mediat :
Bettaieb, Ahmed; Koike, Shinichiro; Chahed, Samah et al. (2017) Podocyte-specific soluble epoxide hydrolase deficiency in mice attenuates acute kidney injury. FEBS J 284:1970-1986
Graves, Joan P; Gruzdev, Artiom; Bradbury, J Alyce et al. (2017) Characterization of the Tissue Distribution of the Mouse Cyp2c Subfamily by Quantitative PCR Analysis. Drug Metab Dispos 45:807-816
Garcia, Victor; Gilani, Ankit; Shkolnik, Brian et al. (2017) 20-HETE Signals Through G-Protein-Coupled Receptor GPR75 (Gq) to Affect Vascular Function and Trigger Hypertension. Circ Res 120:1776-1788
Hanif, Ahmad; Edin, Matthew L; Zeldin, Darryl C et al. (2016) Deletion of soluble epoxide hydrolase enhances coronary reactive hyperemia in isolated mouse heart: role of oxylipins and PPAR?. Am J Physiol Regul Integr Comp Physiol 311:R676-R688

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