Cardiovascular Research Advance Access first published online on July 2, 2008
This version [Corrected Proof] published online on July 22, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn182
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Manganese superoxide dismutase and aldehyde dehydrogenase deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction
,*
1 Second Medical Clinic, Department of Cardiology, Johannes Gutenberg University, Mainz, Germany
2 Molecular Toxicology Group, Department of Biology, University of Konstanz, Konstanz, Germany
3 Department of Dermatology, University of Ulm, Ulm, Germany
4 Department of Environmental Health, University of Occupational and Environmental Health, Iseigaoka 1-1, Yahatanishi, Kitakyushu 807-8555, Japan
5 Department of Medicine, Withaker Boston University School of Medicine, Boston, MA, USA
* Corresponding author: Klinikum der Johannes Gutenberg-Universität Mainz, II. Medizinische Klinik, Labor für Molekulare Kadiologie, Verfügungsgebäude für Forschung und Entwicklung, Raum 00349, Obere Zahlbacher Str. 63, 55101 Mainz, Germany. Tel: +49 6131 3933301; fax: +49 6131 3933304. E-mail address: daiber{at}uni-mainz.de
Aims: 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.
Methods and 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.
Conclusion: The correlation between mtROS formation and acetylcholine-dependent relaxation revealed that mitochondrial radical formation significantly contributes to age-dependent endothelial dysfunction.
KEYWORDS Vascular dysfunction; Mitochondrial oxidative stress; Manganese superoxide dismutase; Mitochondrial aldehyde dehydrogenase; 8-oxodG
Time for primary review: 20 days
P.W. and S.S. contributed equally to this study and should therefore both be considered as first authors. M.M.B. and A.D. contributed equally to this study and should therefore both be considered as senior authors.
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