title: Attenuation of atherogenesis via the anti-inflammatory effects of the selective estrogen receptor beta modulator 8β-VE2.
abstract: BACKGROUND
  Recent studies suggest that modulation of estrogen receptor β (ERβ) may play a crucial role in maintaining vascular homeostasis. We hypothesized that selective ERβ activation will attenuate atherogenesis via anti-inflammatory mechanisms.
  
  
  RESULTS
  Atherosclerosis-prone apoE mice were ovariectomized and then fed a high-cholesterol diet with daily subcutaneous injections of the highly selective and potent ERβ agonist (8β-VE2) for 5 weeks. Compared with controls, treatment with 8β-VE2 reduced aortic arch atherosclerotic lesion areas by 34% of total and 75% of dense lesions, while not altering the serum lipid profile. We attribute these observed vascular effects solely to ERβ modulation as (1) treatment with the nonselective ER antagonist ICI 182,780 completely abrogated the beneficial vascular effects of 8β-VE2 and (2) uterine weight (a sensitive indicator of ERα modulation) did not change with 8β-VE2 treatment. Moreover, mice treated with 8β-VE2 had reduced serum interleukin 1β and tumor necrosis factor α levels. Finally, treatment of macrophages in vitro with 8β-VE2 blocked the uptake of acetylated low-density lipoprotein, suppressed the extracellular levels of the inflammatory cytokine tumor necrosis factor α, and enhanced the extracellular levels of the antiatherogenic/anti-inflammatory protein heat shock protein 27.
  
  
  CONCLUSIONS
  Selective ERβ activation by 8β-VE2 attenuates atherogenesis and is associated with favorable modulation of vascular inflammation.
authors.affiliation: Vascular Biology Laboratory, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, Canada.
authors.forename: Jiangfeng
authors.initials: J
authors.lastname: Sun
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Ma
authors.forename: Yong-Xiang
authors.initials: YX
authors.lastname: Chen
authors.forename: Katey
authors.initials: K
authors.lastname: Rayner
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hibbert
authors.forename: Melissa
authors.initials: M
authors.lastname: McNulty
authors.forename: Bharbhoor
authors.initials: B
authors.lastname: Dhaliwal
authors.forename: Trevor
authors.initials: T
authors.lastname: Simard
authors.forename: Daniel
authors.initials: D
authors.lastname: Ramirez
authors.forename: Edward
authors.initials: E
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000517:prevention & control*; D004195:Disease Models, Animal; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000819:agonists / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D053583:Interleukin-1beta / Q000097:blood; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; D047629:Estrogen Receptor beta; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D000077267:Fulvestrant; D004958:Estradiol