Manganese superoxide dismutase and aldehyde dehydrogenase deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction
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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.
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In one study, 16-month-old MnSOD+/− mice showed elevated reactive oxygen species production and mtDNA damage followed by endothelial dysfunction.
“In one study, 16-month-old MnSOD+/− mice consistently showed elevated ROS production and mtDNA damage, followed by the development of dramatic endothelial dysfunction182.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [182]
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- Authors
- Wenzel, P., Schuhmacher, S., Kienhöfer, J., Müller, J., Hortmann, M., Oelze, M., Schulz, E., Treiber, N., Kawamoto, T., Scharffetter-Kochanek, K., Münzel, T., Bürkle, A., Bachschmid, M. M., & Daiber, A.
- Affiliations
- Johannes Gutenberg University Mainz (DE)
- University of Konstanz (DE)
- Universität Ulm (DE)
- University of Occupational and Environmental Health Japan (JP)
- Boston University (US)
- Corresponding author
- Daiber, Andreas
- ORCID
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-07-02
- Volume
- 80
- Issue
- 2
- Pages
- 280-289
- ISSN
- 0008-6363 (ISSN-L)
- 1755-3245
- PMC
- PMC3937602
- OpenAlex
- W2139020323
- Cited by
- 207
- References
- 45
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 6 · 2023: 6 · 2022: 9 · 2021: 7 · 2020: 8 · 2019: 10 · 2018: 10 · 2017: 14 · 2016: 16 · 2015: 15 · 2014: 17 · 2013: 12 · 2012: 17
- FWCI
- 11.32
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Cardiovascular Research (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- KOPS (University of Konstanz) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Deutsche Herzstiftung
- National Institute on Aging (R01AG027080)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Keywords
- manganese superoxide dismutase, ALDH2, mitochondrial oxidative stress, vascular aging, endothelial dysfunction, mitochondrial reactive oxygen species, mitochondrial DNA damage, vasorelaxation, acetylcholine, nitric oxide, superoxide, aorta
- MeSH terms
- Aldehyde Dehydrogenase, Mitochondrial, Superoxide Dismutase 2, Age Factors, Aging, Aldehyde Dehydrogenase, Animals, Aorta, DNA Damage, DNA, Mitochondrial, Dose-Response Relationship, Drug, Endothelium, Vascular, Male, Mice, Inbred C57BL, Mitochondria, Heart, Muscle, Smooth, Vascular, Superoxide Dismutase, Vasodilation, Vasodilator Agents, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, Mice
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