Abstract 3677: Effects of Aging and Endogenous Extracellular Superoxide Dismutase on Endothelial Function in Mice
A gene variant of extracellular superoxide dismutase (ECSOD) that impairs normal vascular localization is associated with increased risk of ischemic heart disease in people over 70 years old. ECSOD may be reduced with aging and a variety of disease states, and we have reported previously that gene transfer of ECSOD improves endothelial vasomotor function in both old and diseased animals. The role of endogenous/residual levels of ECSOD, however, in modulation of vasomotor function during aging is not clear. Thus, the purpose of this study was to determine whether genetic deletion of endogenous ECSOD predisposes to endothelial dysfunction in old mice. Gene expression (qRT-PCR) and vasomotor function (aortic rings) were measured in adult (10 –12 mo old) and old (28 –31 mo old) wild type (ECSOD+/+) and ECSOD knockout (ECSOD−/−) mice. Compared to young ECSOD+/+ mice, expression of ECSOD, but not CuZnSOD or MnSOD, was reduced in old ECSOD+/+ animals by 40±8% (mean±SE, p < 0.05). No compensatory changes in expression of other SOD isoforms were observed in ECSOD−/− mice. In WT mice there was mild impairment in maximum relaxation to acetylcholine during aging (young ECSOD+/+ = 89±2%, old ECSOD+/+ = 75±4%, p < 0.05). Genetic deletion of ECSOD produced mild impairment in maximal relaxation to acetylcholine (10−4) in young adult ECSOD-deficient mice (75 ± 3%) compared to young adult wild type mice (p < 0.05). We observed profound impairment in endothelial function in old ECSOD−/− mice (47 ± 5%, p < 0.05). Relaxation to acetylcholine was not improved by Tempol in young ECSOD+/+ or ECSOD−/−mice, or in old ECSOD+/+ mice. Tempol, however, improved endothelial function in old ECSOD−/− mice (47 3 ± vs 71 ± 5%, p < 0.05). Maximal relaxation to sodium nitroprusside was similar in aorta in all groups of mice. We conclude that, although ECSOD declines substantially during aging and is associated with mild endothelial function in old wild-type mice, the residual levels of endogenous ECSOD play a critical role in determining bioavailability of nitric oxide and protection against endothelial dysfunction during aging.