Abstract 17314: Free Radical-Dependent Sod2 Promoter Demethylation is Associated with Healthy Vascular Aging
BACKGROUND: Free radicals are important signaling molecules but whether they contribute to epigenetic-dependent regulation of vascular function during aging is unknown. We hypothesized that the normal metabolism-derived free radical production induces epigenetic regulations at the promoter region of antioxidant enzymes, promoting their up-regulation and thus, delays healthy age-associated vascular damage and endothelial dysfunction.
METHODS: Mice were treated (n=12) or not (control; CTL, n=12) with the antioxidant catechin (CAT; 30mg/kg/d) from weaning to the age of 9 months (9m); 6 mice from each group were then kept untreated until the age of 12 months (12m). At sacrifice (9 or 12m), femoral arteries were isolated to study endothelial function characterized by acetylcholine (Ach)-induced dilation in pressurized (100 mm Hg) vessels, and for DNA extraction to quantify Sod2 gene promoter methylation (EpiTYPER, Sequenom). The abdominal aorta was isolated to measure mRNA Sod2 levels (qPCR). Results are mean±SEM.
RESULTS: At 9m, Ach-induced dilation was similar in CTL (87±5%) and CAT-treated (94±2%) mice. After inhibition of NO synthase (NOS), however, Ach-induced NO-independent dilatation was reduced (P<0.05) in CTL mice (33±16%) but not in CAT-treated mice (81±9%). These differences were maintained at 12m. These functional changes suggest that normal oxidative stress impairs NO-independent compensatory dilation at 9m without further degradation at 12m. In CTL mice, Sod2 promoter methylation decreased from the age of 9 to 12m (from 16±2% to 7±1%; P<0.05); this was prevented by CAT (15±3% and 14±3%, at 9 and 12m, respectively) suggesting that free radicals lead to an epigenetic-dependent up-regulation of Sod2 expression. Accordingly, Sod2 mRNA expression was similar at 9m but greater at 12m in CTL (1.39±0.12 a.u.; P<0.05) compared to CAT-treated (0.31±0.06) mice. Hence, scavenging free radicals with CAT prevented the epigenetic-dependent up-regulation of compensatory Sod2 expression.
CONCLUSION: Free radical-dependent Sod2 promoter demethylation is associated with healthy vascular aging; this could contribute to minimizing the rise in oxidative stress-dependant damage and delay endothelial dysfunction.
- © 2011 by American Heart Association, Inc.