Abstract 18268: Jund is a Critical Modulator of Oxidative Stress-induced Vascular Aging

Background. Reactive oxygen species (ROS) are the major determinant of vascular aging. JunD, a member of the activated protein 1 (AP-1) family of transcription factors, promotes the intracellular redox homeostasis. The present study investigates the role of JunD in aging-associated endothelial dysfunction. Methods and Results . Blunted vasorelaxation was found in young and old JunD -/- mice as compared with age-matched WT animals [maximal relaxations were 51±1.5 %vs 83±4.8 (young) and 34±2.3 vs 58±2.4 (old) for JunD -/- and WT mice, respectively, n=6-8, p<0.05 vs age-matched group]. ROS scavengers superoxide dismutase (PEG-SOD) and catalase restored endothelial function. Accordingly, JunD-/- mice displayed not only an age-independent decline of NO release but also increased superoxide and peroxynitrite levels in endothelial cells assessed by chemoluminescence. Nitrotyrosine residues, identified by immunofluorescence, were also elevated. ROS scavenging enzymes manganese (Mn) and extracellular (ec) SOD, aldehyde dehydrogenase-2 and glutathione peroxidase-1(GPx-1) were downregulated in JunD -/- mice. In contrast, NADPH oxidase subunit p47phox was upregulated. Furthermore, in JunD-/- mice eNOS expression and eNOS activating Ser-1177 phosphorylation were reduced. Interestingly, age-induced endothelial dysfunction was paralleled by a significant reduction of JunD protein expression in old as compared with young WT mice. In human aortic endothelial cells, siRNA-mediated JunD knockdown elicited a similar impairment of NO/O2- production, which was abolished by simultaneous silencing of p47phox. Notably, JunD mRNA expression was reduced in peripheral monocytes from old compared with young healthy blood donors (63.30 ± 6.0 vs 113.9 ± 6.7, respectively, values normalized to TBP mRNA, n=6; p< 0.0004), and correlated with gene expression of MnSOD (r=0.65, p<0.05). Conclusions. Aging-induced oxidative stress and endothelial dysfunction were markedly accelerated in JunD -/- mice compared with age-matched WT littermates. JunD may be a crucial modulator of ROS-mediated vascular aging, representing a novel molecular target to slow down this process.