MnSOD and ALDH‐2 deficiency potentiate aging‐associated vascular dysfunction, mitochondrial oxidative stress and mtDNA strand breaks

Abstract

Vascular aging is associated with progressive deterioration of vascular homeostasis and reduced relaxation. These effects can be explained by a reduction in free bioavailable NO that is inactivated by an age‐dependent increase in superoxide formation. In the present study mitochondria as a source of reactive oxygen species (ROS) and the contribution of manganese superoxide dismutase (MnSOD) and aldehyde dehydrogenase (ALDH‐2) were investigated. Age‐dependent effects on vascular function were determined in aortae of these mice by isometric tension measurements. Mitochondrial ROS formation was measured by enhanced chemiluminescence in isolated heart mitochondria. ROS‐mediated mitochondrial DNA (mtDNA) damages were detected by the fluorescent‐detection alkaline DNA unwinding (FADU)‐assay. Expression of antioxidant proteins were assayed by quantitative RT‐PCR. Endothelial dysfunction was observed in aged C57/Bl6 WT mice in parallel to increased mitochondrial ROS formation and mtDNA damage. In contrast, middle‐aged ALDH‐2−/− mice showed a marked vascular dysfunction that was similar in old ALDH‐2−/− mice. Aged MnSOD+/− mice showed the most pronounced phenotype such as severely impaired vasorelaxation, highest levels of mitochondrial ROS formation and mtDNA damage. Mitochondrial radical formation significantly contributes to age‐dependent endothelial‐dysfunction.