Abstract 169: Genetic Deletion of JunD Enhances Age-Associated Endothelial Dysfunction
Enhanced production of reactive oxygen species (ROS) is the major determinant of age-related endothelial dysfunction. JunD, a member of the AP-1 family of transcription factors, regulates genes involved in antioxidant defense. The present study was design to investigate whether JunD deficient mice (JunD −/ −) are more prone to age-related endothelial dysfunction in comparison to age-matched wild type (WT) mice. Thoracic aortic rings from young (3 months old), middle aged (6 months old) and old (12 months old) male JunD−/ − and WT mice were suspended for isometric tension recording. Endothelium-dependent relaxation to acetylcholine (Ach, 10−9-10−6mol/L)) was assessed after submaximal contraction with norepinephrine (10−6mol/L). To evaluate the level of oxidative stress in JunD−/ − and WT mice of different age, superoxide anion (O2−) concentration in aortic tissue was determined by using a coelenterazine-enhanced chemiluminescence method. The age-associated impairment of endothelium-dependent relaxations to Ach was significantly enhanced in 6 month old JunD−/ − as compared to age-matched WT (max relaxation: 55±5 vs 78±4%, respectively, n=8, p<0.05). At 12 months the max relaxations to Ach were 40±3 vs 58±2% for JunD−/ − and WT mice, respectively (n=8, p<0.05). Endothelium-independent relaxations to sodium nitroprusside did not differ in JunD−/ − and WT of different age groups (n=7, p<NS). O2− generation was significantly higher in JunD−/ − mice as compared to WT already at 6 months of age (15218±2699 vs 9247±950 RLU, n=3–5, p<0.05). Accordingly, the impaired relaxations to Ach were restored by free radical scavengers superoxide dismutase (150 U/ml) as well as catalase (1200 U/ml). Our results show that JunD gene plays a crucial role in the cellular defence against age-dependent, ROS-mediated vascular aging.