Editors' ChoiceVascular Biology

Insights into Aging Vessels

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Science Translational Medicine  27 Feb 2013:
Vol. 5, Issue 174, pp. 174ec37
DOI: 10.1126/scitranslmed.3005909

Reactive oxygen species such as superoxide anion (O) and hydrogen peroxide (H2O2) are both a blessing and a curse. When in balance, these radicals engage in biological functions such as signal transduction. However, an increase in cellular oxidative stress leading to an increase in these reactive oxygen species has been associated with numerous chronic diseases. Now, a new research study by Paneni and colleagues adds to our understanding of how oxidative stress is connected to vascular health. Earlier findings identified JunD, a transcription factor in the AP-1 (activated protein-1) family, as a key player in this connection. Using mice with a genetic deletion of JunD (JunD–/– mice), the researchers found that the impairment of endothelium-dependent vasorelaxation in young JunD–/– mice (6 months of age) was similar to that in old control mice (22 months of age). This endothelial dysfunction was even more pronounced in old JunD–/– mice as compared with age-matched control animals. Scavenging reactive oxygen species in these experiments restored normal vascular function in the young JunD–/– mice and old control mice, suggesting that JunD function strikes a balance with free radicals to ensure endothelial health. In support of this notion, the researchers showed that oxidative stress in the mitochondria of tissue slices from the aorta of young JunD–/– mice was as high as that in the old control mice; an even greater increase was evident in old JunD–/– mice. Age seemed to be driving the decrease in JunD function, with the methylation of its promotor as a likely mechanism. The loss in endothelial cell function in older mice was rescued by overexpression of JunD. Deletion of JunD in endothelial cells of the aorta or JunD down-regulation by small interfering RNAs (siRNAs) disturbed the balance between pro- and antioxidant activities, resulting in accelerated vascular aging as indicated by reduced telomerase activity.

Two further experiments support the role of JunD in human vascular homeostasis. First, siRNA-silenced JunD expression in human aortic endothelial cells resulted in excess production of free radicals. Second, JunD gene and protein expression was much lower in peripheral blood mononuclear cells from 60-year-olds as compared with volunteers in their 20s. Taken together, these data suggest that JunD function might mechanistically link oxidative stress and vascular aging. But as the authors note, it remains to be seen whether JunD can be developed into a pharmacological opportunity to mitigate cardiovascular risk.

F. Paneni et al., Deletion of the AP-1 transcription factor JunD induces oxidative stress and accelerates age-related endothelial dysfunction. Circulation, published online 14 February 2013 (10.1161/​CIRCULATIONAHA.112.000826) [Abstract]

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