title: Combined deficiency in glutathione peroxidase 4 and vitamin E causes multiorgan thrombus formation and early death in mice.
abstract: BACKGROUND
  Growing evidence indicates that oxidative stress contributes markedly to endothelial dysfunction. The selenoenzyme glutathione peroxidase 4 (Gpx4) is an intracellular antioxidant enzyme important for the protection of membranes by its unique activity to reduce complex hydroperoxides in membrane bilayers and lipoprotein particles. Yet a role of Gpx4 in endothelial cell function has remained enigmatic.
  
  
  OBJECTIVE
  To investigate the role of Gpx4 ablation and subsequent lipid peroxidation in the vascular compartment in vivo.
  
  
  RESULTS
  Endothelium-specific deletion of Gpx4 had no obvious impact on normal vascular homeostasis, nor did it impair tumor-derived angiogenesis in mice maintained on a normal diet. In stark contrast, aortic explants from endothelium-specific Gpx4 knockout mice showed a markedly reduced number of endothelial branches in sprouting assays. To shed light onto this apparent discrepancy between the in vivo and ex vivo results, we depleted mice of a second antioxidant, vitamin E, which is normally absent under ex vivo conditions. Therefore, mice were fed a vitamin E-depleted diet for 6 weeks before endothelial deletion of Gpx4 was induced by 4-hydroxytamoxifen. Surprisingly, ≈80% of the knockout mice died. Histopathological analysis revealed detachment of endothelial cells from the basement membrane and endothelial cell death in multiple organs, which triggered thrombus formation. Thromboembolic events were the likely cause of various clinical pathologies, including heart failure, renal and splenic microinfarctions, and paraplegia.
  
  
  CONCLUSIONS
  Here, we show for the first time that in the absence of Gpx4, sufficient vitamin E supplementation is crucial for endothelial viability.
authors.affiliation: Walter Brendel Centre of Experimental Medicine, Munich Heart Alliance, Munich Cluster for Systems Neurology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Wortmann
authors.forename: Manuela
authors.initials: M
authors.lastname: Schneider
authors.forename: Joachim
authors.initials: J
authors.lastname: Pircher
authors.forename: Juliane
authors.initials: J
authors.lastname: Hellfritsch
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.forename: Naidu
authors.initials: N
authors.lastname: Vegi
authors.forename: Pirkko
authors.initials: P
authors.lastname: Kölle
authors.forename: Peter
authors.initials: P
authors.lastname: Kuhlencordt
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pohl
authors.forename: Georg W
authors.initials: GW
authors.lastname: Bornkamm
authors.forename: Marcus
authors.initials: M
authors.lastname: Conrad
authors.forename: Heike
authors.initials: H
authors.lastname: Beck
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005979:Glutathione Peroxidase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D006339:Heart Rate / Q000502:physiology; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018384:Oxidative Stress / Q000502:physiology; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D013927:Thrombosis / Q000209:etiology* / Q000401:mortality* / Q000503:physiopathology; D014810:Vitamin E / Q000235:genetics* / Q000378:metabolism; D014811:Vitamin E Deficiency / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D014810:Vitamin E; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase
keywords: endothelium, vascular; oxidant stress; thrombosis; vascular endothelial function; α-tocopherol