title: Deletion of the activated protein-1 transcription factor JunD induces oxidative stress and accelerates age-related endothelial dysfunction.
abstract: BACKGROUND
  Reactive oxygen species are major determinants of vascular aging. JunD, a member of the activated protein-1 family of transcription factors, is emerging as a major gatekeeper against oxidative stress. However, its contribution to reactive oxygen species homeostasis in the vasculature remains unknown.
  
  
  RESULTS
  Endothelium-dependent vasorelaxation was impaired in young and old JunD(-/-) mice (6 and 22 months old) compared with age-matched wild-type mice. JunD(-/-) mice displayed an age-independent decline in endothelial nitric oxide release and endothelial nitric oxide synthase activity and increased mitochondrial superoxide formation and peroxynitrite levels. Furthermore, vascular expression and activity of the free radical scavengers manganese and extracellular superoxide dismutase and aldehyde dehydrogenase 2 were reduced, whereas the NADPH oxidase subunits p47phox, Nox2, and Nox4 were upregulated. These redox changes were associated with premature vascular aging, as shown by reduced telomerase activity, increased β-galactosidase-positive cells, upregulation of the senescence markers p16(INK4a) and p53, and mitochondrial disruption. Interestingly, old wild-type mice showed a reduction in JunD expression and transcriptional activity resulting from promoter hypermethylation and binding with tumor suppressor menin, respectively. In contrast, JunD overexpression blunted age-induced endothelial dysfunction. In human endothelial cells, JunD knockdown exerted a similar impairment of the O2(-)/nitric oxide balance that was prevented by concomitant NADPH inhibition. In parallel, JunD expression was reduced in monocytes from old versus young healthy subjects and correlated with mRNA levels of scavenging and oxidant enzymes.
  
  
  CONCLUSIONS
  JunD provides protection in aging-induced endothelial dysfunction and may represent a novel target to prevent reactive oxygen species-driven vascular aging.
authors: Cardiology and Cardiovascular Research, Institute of Physiology and University Hospital, Zürich, Switzerland.
authors: Francesco
authors: F
authors: Paneni
authors: Elena
authors: E
authors: Osto
authors: Sarah
authors: S
authors: Costantino
authors: Bogdan
authors: B
authors: Mateescu
authors: Sylvie
authors: S
authors: Briand
authors: Giuseppe
authors: G
authors: Coppolino
authors: Enrico
authors: E
authors: Perna
authors: Pavani
authors: P
authors: Mocharla
authors: Alexander
authors: A
authors: Akhmedov
authors: Ruslan
authors: R
authors: Kubant
authors: Lucia
authors: L
authors: Rohrer
authors: Tadeusz
authors: T
authors: Malinski
authors: Giovanni G
authors: GG
authors: Camici
authors: Christian M
authors: CM
authors: Matter
authors: Fatima
authors: F
authors: Mechta-Grigoriou
authors: Massimo
authors: M
authors: Volpe
authors: Thomas F
authors: TF
authors: Lüscher
authors: Francesco
authors: F
authors: Cosentino
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D017353:Gene Deletion; D006706:Homeostasis / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology; D023421:Models, Animal; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D017382:Reactive Oxygen Species; C528955:junD protein, mouse; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase