11,12-Epoxyecosatrienoic acids mitigate endothelial dysfunction associated with estrogen loss and aging: Role of membrane depolarization

Chongxiu Sun, Scott I. Simon, Greg A. Foster, Christopher E. Radecke, Hyun Tae V Hwang, Xiaodong Zhang, Bruce D. Hammock, N. Chiamvimonvat, Anne A. Knowlton

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Objective: 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. Approach/results: When stabilized by an sEH inhibitor (seHi), 11,12-EET at a physiologically low dose (0.1 nM) 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)180-188
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume94
DOIs
StatePublished - May 1 2016

Keywords

  • Adhesion
  • Aging
  • EETs
  • Endothelial cell
  • Estrogen
  • Inflammation
  • Vascular

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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