Cardiovascular Research Advance Access [Accepted Manuscript] published online on July 2, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn182
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MnSOD and ALDH-2 deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction
1 2nd Medical Clinic, Dept. of Cardiology, Johannes Gutenberg University, Mainz, Germany
2 Molecular Toxicology Group, Department of Biology, University of Konstanz, Germany
3 Department of Dermatology, University of 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, MA, USA
¶ Address correspondence to: Dr. Andreas Daiber, 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, Phone +49 (0)6131 33301, Fax +49 (0)6131 33304, E-mail: 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 for 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: 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.
Results: Endothelial dysfunction was observed in aged C57/Bl6 WT mice in parallel to increased mitochondrial ROS formation and oxidative mitochondrial DNA 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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