title: Manganese superoxide dismutase and aldehyde dehydrogenase deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction.
abstract: OBJECTIVE
  Imbalance between pro- and antioxidant species (e.g. during aging) plays a crucial role for vascular function and is associated with oxidative gene regulation and modification. Vascular aging is associated with progressive deterioration of vascular homeostasis leading to reduced relaxation, hypertrophy, and a higher risk of thrombotic events. These effects can be explained by a reduction in free bioavailable nitric oxide 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, SOD-2) and aldehyde dehydrogenase (ALDH-2) were investigated.
  
  
  RESULTS
  Age-dependent effects on vascular function were determined in aortas of C57/Bl6 wild-type (WT), ALDH-2(-/-), MnSOD(+/+), and MnSOD(+/-) mice by isometric tension measurements in organ chambers. Mitochondrial ROS formation was measured by luminol (L-012)-enhanced chemiluminescence and 2-hydroxyethidium formation with an HPLC-based assay in isolated heart mitochondria. ROS-mediated mitochondrial DNA (mtDNA) damage was detected by a novel and modified version of the fluorescent-detection alkaline DNA unwinding (FADU) assay. Endothelial dysfunction was observed in aged C57/Bl6 WT mice in parallel to increased mitochondrial ROS formation and oxidative mtDNA damage. In contrast, middle-aged ALDH-2(-/-) mice showed a marked vascular dysfunction that was similar in old ALDH-2(-/-) mice suggesting that ALDH-2 exerts age-dependent vasoprotective effects. Aged MnSOD(+/-) mice showed the most pronounced phenotype such as severely impaired vasorelaxation, highest levels of mitochondrial ROS formation and mtDNA damage.
  
  
  CONCLUSIONS
  The correlation between mtROS formation and acetylcholine-dependent relaxation revealed that mitochondrial radical formation significantly contributes to age-dependent endothelial dysfunction.
authors.affiliation: Second Medical Clinic, Department of Cardiology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
authors.forename: Swenja
authors.initials: S
authors.lastname: Schuhmacher
authors.forename: Joachim
authors.initials: J
authors.lastname: Kienhöfer
authors.forename: Johanna
authors.initials: J
authors.lastname: Müller
authors.forename: Marcus
authors.initials: M
authors.lastname: Hortmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schulz
authors.forename: Nicolai
authors.initials: N
authors.lastname: Treiber
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Karin
authors.initials: K
authors.lastname: Scharffetter-Kochanek
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Alexander
authors.initials: A
authors.lastname: Bürkle
authors.forename: Markus Michael
authors.initials: MM
authors.lastname: Bachschmid
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
mesh_terms: D000367:Age Factors; D000375:Aging; D000444:Aldehyde Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000201:enzymology*; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000503:physiopathology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D000099156:Superoxide Dismutase 2
chemical_list: D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D014665:Vasodilator Agents; D000099156:Superoxide Dismutase 2; C515029:ALDH2 protein, mouse