title: 11,12-Epoxyecosatrienoic acids mitigate endothelial dysfunction associated with estrogen loss and aging: Role of membrane depolarization.
abstract: Endothelial dysfunction, including upregulation of inflammatory adhesion molecules and impaired vasodilatation, is a key element in cardiovascular disease. Aging and estrogen withdrawal in women are associated with endothelial inflammation, vascular stiffness and increased cardiovascular disease. Epoxyecosatrienoic acids (EETs), the products of arachidonic acid metabolism mediated by cytochrome P450 (CYP) 2J, 2C and other isoforms, are regulated by soluble epoxide hydrolase (sEH)-catalyzed conversion into less active diols. We hypothesized that 11,12-EETs would reduce the endothelial dysfunction associated with aging and estrogen loss.
  
  
  
  When stabilized by an sEH inhibitor (seHi), 11,12-EET at a physiologically low dose (0.1nM) reduced cytokine-stimulated upregulation of adhesion molecules on human aorta endothelial cells (HAEC) and monocyte adhesion under shear flow through marked depolarization of the HAEC when combined with TNFα. Mechanistically, neither 11,12-EETs nor 17β-estradiol (E2) at physiologic concentrations prevented activation of NFκB by TNFα. E2 at physiological concentrations reduced sEH expression in HAEC, but did not alter CYP expression, and when combined with TNFα depolarized the cell. We also examined vascular dysfunction in adult and aged ovariectomized Norway brown rats (with and without E2 replacement) using an ex-vivo model to analyze endothelial function in an intact segment of artery. sEHi and 11,12-EET with or without E2 attenuated phenylephrine induced constriction and increased endothelial-dependent dilation of aortic rings from ovariectomized rats.
  
  
  
  Increasing 11,12-EETs through sEH inhibition effectively attenuates inflammation and may provide an effective strategy to preserve endothelial function and prevent atherosclerotic heart disease in postmenopausal women.
authors.affiliation: The Department of Veterans Affairs, Northern California VA, Sacramento, CA, United States; Molecular & Cellular Cardiology, Cardiovascular Division, Department of Medicine, University of California, Davis, Davis, CA, United States; Department of Biomedical Engineering, University of California, Davis, Davis, CA, United States.
authors.forename: Chongxiu
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Biomedical Engineering, University of California, Davis, Davis, CA, United States.
authors.forename: Scott I
authors.initials: SI
authors.lastname: Simon
authors.affiliation: Department of Biomedical Engineering, University of California, Davis, Davis, CA, United States.
authors.forename: Greg A
authors.initials: GA
authors.lastname: Foster
authors.affiliation: Department of Biomedical Engineering, University of California, Davis, Davis, CA, United States.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Radecke
authors.affiliation: The Department of Veterans Affairs, Northern California VA, Sacramento, CA, United States; Molecular & Cellular Cardiology, Cardiovascular Division, Department of Medicine, University of California, Davis, Davis, CA, United States.
authors.forename: HyunTae V
authors.initials: HV
authors.lastname: Hwang
authors.affiliation: Molecular & Cellular Cardiology, Cardiovascular Division, Department of Medicine, University of California, Davis, Davis, CA, United States.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Entomology and Nematology, University of California, Davis, Davis, CA, United States; Comprehensive Cancer Center, University of California, Davis, Davis, CA, United States.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: The Department of Veterans Affairs, Northern California VA, Sacramento, CA, United States; Molecular & Cellular Cardiology, Cardiovascular Division, Department of Medicine, University of California, Davis, Davis, CA, United States.
authors.forename: N
authors.initials: N
authors.lastname: Chiamvimonvat
authors.affiliation: The Department of Veterans Affairs, Northern California VA, Sacramento, CA, United States; Molecular & Cellular Cardiology, Cardiovascular Division, Department of Medicine, University of California, Davis, Davis, CA, United States; Department of Pharmacology, University of California, Davis, Davis, CA, United States. Electronic address: aaknowlton@ucdavis.edu.
authors.forename: Anne A
authors.initials: AA
authors.lastname: Knowlton
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000375:Aging / Q000378:metabolism*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D013314:Stress, Mechanical; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D059289:Vascular Stiffness
chemical_list: D004967:Estrogens; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; D015126:8,11,14-Eicosatrienoic Acid
keywords: Adhesion; Aging; EETs; Endothelial cell; Estrogen; Inflammation; Vascular