Manganese superoxide dismutase and aldehyde dehydrogenase deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction

Wenzel, Philip; Schuhmacher, Swenja; Kienhöfer, J; Müller, Johanna; Hortmann, Marcus; Oelze, Matthias; Schulz, Eberhard; Treiber, Nicolai; Kawamoto, Toshihiro; Scharffetter‐­Kochanek, Karin; Münzel, Thomas; Bürkle, Alexander; Bachschmid, Markus; Daiber, Andreas

doi:10.1093/cvr/cvn182

Cited by 190 publications

(173 citation statements)

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“…Mitochondrial decay is evident during normal aging of tissues as well and causes the cell's anti-stress pathways to operate with less efficiency [26][27][28]. Specifically, alterations in cytoplasmic Cu/Zn-superoxide dismutase (SOD), lipid peroxidation, mitochondrial Mn-SOD, and oxidative stress markers have been observed [27,28].…”

Section: Introductionmentioning

confidence: 99%

Mitochondria impairment correlates with increased sensitivity of aging RPE cells to oxidative stress

Burke

et al. 2010

j ocul biol dis inform

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Impairment of mitochondria function and cellular antioxidant systems are linked to aging and neurodegenerative diseases. In the eye, the retinal pigment epithelium (RPE) is exposed to a highly oxidative environment that contributes to age-related visual dysfunction. Here, we examined changes in mitochondrial function in human RPE cells and sensitivity to oxidative stress with increased chronological age. Primary RPE cells from young (9-20)-, mid-age (48-60)-, and >60 (62-76)-year-old donors were grown to confluency and examined by electron microscopy and flow cytometry using several mitochondrial functional assessment tools. Susceptibility of RPE cells to H 2 O 2 toxicity was determined by lactate dehydrogenase and cytochrome c release, as well as propidium iodide staining. Reactive oxygen species, cytoplasmic Ca 2+ [Ca 2+ ] c , and mitochondrial Ca 2+ [Ca 2+ ] m levels were measured using 2′,7′-dichlorodihydrofluorescein diacetate, fluo-3/AM, and Rhod-2/AM, respectively, adenosine triphosphate (ATP) levels were measured by a luciferin/luciferase-based assay and mitochondrial membrane potential (ΔΨm) estimated using 5,5′,6,6′-tetrachloro 1,1′3,3′-tetraethylbenzimid azolocarbocyanine iodide. Expression of mitochondrial and antioxidant genes was determined by real-time polymerase chain reaction. RPE cells show greater sensitivity to oxidative stress, reduction in expression of mitochondrial heat shock protein 70, uncoupling protein 2, and superoxide dismutase 3, and greater expression of superoxide dismutase 2 levels with increased chronological age. Changes in mitochondrial number, size, shape, matrix density, cristae architecture, and membrane integrity were more prominent in samples obtained from >60 years old compared to midage and younger donors. These mitochondria abnormalities correlated with lower ATP levels, reduced ΔΨm, decreased [Ca 2+ ] c , and increased sequestration of [Ca 2+ ] m in cells with advanced aging. Our study provides evidence for mitochondrial decay, bioenergetic deficiency, weakened antioxidant defenses, and increased sensitivity of RPE cells to oxidative stress with advanced aging. Our findings suggest that with increased severity of mitochondrial decay and oxidative stress, RPE function may be altered in some individuals in a way that makes the retina more susceptible to age-related injury.

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Section: Introductionmentioning

confidence: 99%

Mitochondria impairment correlates with increased sensitivity of aging RPE cells to oxidative stress

Burke

et al. 2010

j ocul biol dis inform

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“…2 This observation points to a strong correlation between aging, oxidative stress, and, as a consequence, development of vascular/endothelial dysfunction.…”

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confidence: 97%

“…1 Increased oxidative stress from mitochondria and other enzymatic sources as well as vascular dysfunction manifest in aged animals. 2 This observation points to a strong correlation between aging, oxidative stress, and, as a consequence, development of vascular/endothelial dysfunction. 3 In 1954, Harman 4 expressed for the first time the free radical theory of aging.…”

mentioning

confidence: 97%

“…2 This observation points to a strong correlation between aging, oxidative stress, and, as a consequence, development of vascular/endothelial dysfunction.3 In 1954, Harman 4 expressed for the first time the free radical theory of aging. The prevailing hypothesis is that an age-dependent increase in We have previously shown that genetic deletion of the mitochondrial antioxidant proteins manganese superoxide dismutase and aldehyde dehydrogenase-2 contributes to aging-dependent vascular dysfunction and mitochondrial oxidative stress.…”

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confidence: 99%

“…5 We have previously shown that genetic deletion of the mitochondrial antioxidant proteins manganese superoxide dismutase and aldehyde dehydrogenase-2 contributes to aging-dependent vascular dysfunction and mitochondrial oxidative stress. 2 It is worth noting and of high clinical importance that antioxidant enzymes have a significant effect on the healthspan of animals during normal aging (eg, indicated by less aging-associated cardiovascular complications during the sunset years) and also on the resistance to stress conditions. 6 Previous studies have revealed increased mitochondrial and systemic oxidative stress in glutathione peroxidase-1 (GPx-1)-ablated mice 7 and synergistic negative effects on vascular function in the setting of hyperlipidemia, 8 diabetes mellitus, 9 and hypertension.…”

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confidence: 99%

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Glutathione Peroxidase-1 Deficiency Potentiates Dysregulatory Modifications of Endothelial Nitric Oxide Synthase and Vascular Dysfunction in Aging

et al. 2014

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390T he incidence and frequency of cardiovascular diseases, such as hypertension, diabetes mellitus, and myocardial infarction, increase substantially with age.1 Increased oxidative stress from mitochondria and other enzymatic sources as well as vascular dysfunction manifest in aged animals. 2 This observation points to a strong correlation between aging, oxidative stress, and, as a consequence, development of vascular/endothelial dysfunction.3 In 1954, Harman 4 expressed for the first time the free radical theory of aging. The prevailing hypothesis is that an age-dependent increase in We have previously shown that genetic deletion of the mitochondrial antioxidant proteins manganese superoxide dismutase and aldehyde dehydrogenase-2 contributes to aging-dependent vascular dysfunction and mitochondrial oxidative stress.2 It is worth noting and of high clinical importance that antioxidant enzymes have a significant effect on the healthspan of animals during normal aging (eg, indicated by less aging-associated cardiovascular complications during the sunset years) and also on the resistance to stress conditions. 6 Previous studies have revealed increased mitochondrial and systemic oxidative stress in glutathione peroxidase-1 (GPx-1)-ablated mice 7 and synergistic negative effects on vascular function in the setting of hyperlipidemia, 8 diabetes mellitus, 9 and hypertension. 10 Moreover, increased senescence was demonstrated for fibroblasts from GPx-1 −/− mice. 7 Most importantly, a correlation between GPx-1 activity in blood cells andAbstract-Recently, we demonstrated that gene ablation of mitochondrial manganese superoxide dismutase and aldehyde dehydrogenase-2 markedly contributed to age-related vascular dysfunction and mitochondrial oxidative stress. The present study has sought to investigate the extent of vascular dysfunction and oxidant formation in glutathione peroxidase-1-deficient (GPx-1 −/− ) mice during the aging process with special emphasis on dysregulation (uncoupling) of the endothelial NO synthase. GPx-1 −/− mice on a C57 black 6 (C57BL/6) background at 2, 6, and 12 months of age were used. Vascular function was significantly impaired in 12-month-old GPx-1 −/− -mice as compared with age-matched controls. Oxidant formation, detected by 3-nitrotyrosine staining and dihydroethidine-based fluorescence microtopography, was increased in the aged GPx-1 −/− mice. Aging per se caused a substantial protein kinase C-and protein tyrosine kinase-dependent phosphorylation as well as S-glutathionylation of endothelial NO synthase associated with uncoupling, a phenomenon that was more pronounced in aged GPx-1 −/− mice. GPx-1 ablation increased adhesion of leukocytes to cultured endothelial cells and CD68 and F4/80 staining in cardiac tissue. Aged GPx-1 −/− mice displayed increased oxidant formation as compared with their wild-type littermates, triggering redox-signaling pathways associated with endothelial NO synthase dysfunction and uncoupling. Thus, our data demonstrate that aging leads to decreased NO bioavailabi...

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High‐Throughput Assays to Quantify the Formation of DNA Strand Breaks

Moreno‐Villanueva

Bürkle

2013

High‐Throughput Screening Methods in Toxicity Testing

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Manganese superoxide dismutase and aldehyde dehydrogenase deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction

Abstract: The correlation between mtROS formation and acetylcholine-dependent relaxation revealed that mitochondrial radical formation significantly contributes to age-dependent endothelial dysfunction.

Cited by 190 publications

References 43 publications

Mitochondria impairment correlates with increased sensitivity of aging RPE cells to oxidative stress

Mitochondria impairment correlates with increased sensitivity of aging RPE cells to oxidative stress

Glutathione Peroxidase-1 Deficiency Potentiates Dysregulatory Modifications of Endothelial Nitric Oxide Synthase and Vascular Dysfunction in Aging

High‐Throughput Assays to Quantify the Formation of DNA Strand Breaks

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