Deletion of the activated protein-1 transcription factor JunD induces oxidative stress and accelerates age-related endothelial dysfunction

Francesco Paneni, Elena Osto, Sarah Costantino, Bogdan Mateescu, Sylvie Briand, Giuseppe Coppolino, Enrico Perna, Pavani Mocharla, Alexander Akhmedov, Ruslan Kubant, Lucia Rohrer, Tadeusz Malinski, Giovanni G. Camici, Christian M. Matter, Fatima Mechta-Grigoriou, Massimo Volpe, Thomas F. Lüscher, Francesco Cosentino

Research output: Contribution to journalArticlepeer-review

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. Methods and 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 p16INK4a 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.

Original languageEnglish
Pages (from-to)1229-1240
Number of pages12
JournalCirculation
Volume127
Issue number11
DOIs
Publication statusPublished - Mar 19 2013

Keywords

  • Aging
  • Endothelial dysfunction
  • Oxidative stress
  • Vascular biology

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

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