Deletion of the AP-1 Transcription Factor JunD Induces Oxidative Stress and Accelerates Age-Related Endothelial Dysfunction

BACKGROUND: Reactive oxygen species (ROS) are major determinants of vascular aging. JunD, a member of the activated protein 1 (AP-1) family of transcription factors, is emerging as a major gatekeeper against oxidative stress. However, its contribution to ROS homeostasis in the vasculature remains unknown. METHODS AND RESULTS: Endothelium-dependent vasorelaxation was impaired in young and old JunD-/- mice (6 and 22 month old) as compared with age-matched wild-type (WT). JunD-/- mice displayed an age-independent decline of endothelial NO release and eNOS activity as well as increased mitochondrial superoxide formation and peroxynitrite levels. Furthermore, vascular expression and activity of free radical scavengers manganese and extracellular superoxide dismutase as well as aldehyde dehydrogenase 2 were reduced while NADPH oxidase subunits p47phox, Nox2 and Nox4 were upregulated. These redox changes were associated with premature vascular aging as shown by reduced teIomerase activity, increased β-gal positive cells, upregulation of senescence markers p16(INK4a ) and p53 as well as mitochondrial disruption. Interestingly, old WT mice showed a reduction of JunD expression and transcriptional activity due to promoter hypermethylation and binding with tumor suppressor menin, respectively. By contrast, JunD overexpression blunted age-induced endothelial dysfunction. In human endothelial cells, JunD knockdown exerted a similar impairment of O(2)(-)/NO balance which was prevented by concomitant NADPH inhibition. In parallel, JunD expression was reduced in monocytes from old vs. 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 ROS-driven vascular aging.