Essential role for the Menkes ATPase in activation of extracellular superoxide dismutase: implication for vascular oxidative stress

Qin, Zhe; Itoh, Shinichi; Jeney, Viktória; Ushio‐Fukai, Masuko; Fukai, Tohru

doi:10.1096/fj.05-4564fje

Cited by 78 publications

(115 citation statements)

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“…The investigators found that ecSOD-specific activity in the conditioned medium from cultured fibroblasts isolated from Atox1 −/− mice or Menkes ATPase mutant mice was decreased markedly and was restored partially by the addition of copper to the conditioned medium. 48,49 Co-immunoprecipitation and in vitro pull-down assays demonstrated a direct interaction between ecSOD and Menkes ATPase, and confocal immunoflurescence microscopy showed co-localization of ecSOD with Menkes ATPase in the trans-Golgi network. 49 These observations suggest that Menkes ATPase transports copper to ecSOD in the trans-Golgi network through a direct physical interaction.…”

Section: Factors Involved In the Regulation Of Ecsod Expression And Amentioning

confidence: 99%

“…48,49 Co-immunoprecipitation and in vitro pull-down assays demonstrated a direct interaction between ecSOD and Menkes ATPase, and confocal immunoflurescence microscopy showed co-localization of ecSOD with Menkes ATPase in the trans-Golgi network. 49 These observations suggest that Menkes ATPase transports copper to ecSOD in the trans-Golgi network through a direct physical interaction. 49 In keeping with these in vitro observations, the aortas of Menkes ATPase mutant mice revealed a decrease in activity of ecSOD in association with a robust increase in levels in vivo.…”

Section: Copper and Copper Transport Pathwaysmentioning

confidence: 99%

“…Fukai and colleagues 48,49 recently determined that copper delivery to ecSOD modulates its enzymatic activity. The investigators found that ecSOD-specific activity in the conditioned medium from cultured fibroblasts isolated from Atox1 −/− mice or Menkes ATPase mutant mice was decreased markedly and was restored partially by the addition of copper to the conditioned medium.…”

Section: Copper and Copper Transport Pathwaysmentioning

confidence: 99%

“…Copper chaperones compete with chelators for copper and directly insert the cofactor into the target apo-cuproenzymes, such as cytochrome C oxidase, SOD1, and Menkes ATPase, thus converting the latter from an inactive to an active state (holo-cuproenzymes The central region of human ecSOD contains the essential amino acid residues involved in the coordination of Cu(II) and Zn(II) ions, which is termed the copper, zinc binding domain. Fukai and colleagues 48,49 recently determined that copper delivery to ecSOD modulates its enzymatic activity. The investigators found that ecSOD-specific activity in the conditioned medium from cultured fibroblasts isolated from Atox1 −/− mice or Menkes ATPase mutant mice was decreased markedly and was restored partially by the addition of copper to the conditioned medium.…”

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confidence: 99%

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Extracellular superoxide dismutase (ecSOD) in vascular biology: an update on exogenous gene transfer and endogenous regulators of ecSOD

Qin

Reszka

Fukai

et al. 2008

Translational Research

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Extracellular superoxide dismutase (ecSOD) is the major extracellular scavenger of superoxide () and a main regulator of nitric oxide (NO) bioactivity in the blood vessel wall, heart, lungs, kidney, and placenta. Involvement of has been implicated in many pathological processes, and removal of extracellular by ecSOD gene transfer has emerged as a promising experimental technique to treat vascular disorders associated with increased oxidant stress. In addition, recent studies have clarified mechanisms that regulate ecSOD expression, tissue binding, and activity, and they have provided new insight into how ecSOD interacts with other factors that regulate vascular function. Finally, studies of a common gene variant in humans associated with disruption of ecSOD tissue binding suggest that displacement of the enzyme from the blood vessel wall may contribute to vascular diseases. The purpose of this review is to summarize recent research findings related to ecSOD function and gene transfer and to stimulate other investigations into the role of this unique antioxidant enzyme in vascular pathophysiology and therapeutics.Oxidative stress induced by superoxide anion ( ) produced in vascular cells is involved in the pathogenesis of cardiovascular and metabolic diseases, including atherosclerosis, 1 ischemia-reperfusion injury, 2 diabetes, 3 hyperlipidemia, 4 and hypertension. 5 Moreover, may also contribute to pulmonary hypertension, 5 erectile dysfunction, 6 cerebral vasospasm, 7 and other disorders associated with vascular dysfunction. Consequently, strategies to reduce levels of have emerged as promising approaches to treating cardiovascular diseases and other conditions associated with enhanced oxidative stress. In mammalian tissues, 3 isoforms of SODs exist: Cu/Zn SOD (SOD1), Mn SOD (SOD2), and extracellular SOD (ecSOD or SOD3). SOD1 is an abundant copper-and zinc-containing cellular protein that is present in the cytosol, nucleus, peroxisomes, and mitochondrial inner membrane. Its primary function is to lower the intracellular steady-state concentration of . SOD1 mutations are associated with neural diseases such as amyotrophic lateral sclerosis. 8 SOD2 is a mitochondrial enzyme that disposes of generated by respiratory chain activity. SOD2 can be induced to protect against prooxidant insults. Conversely, SOD2 activity is decreased in physiologic aging and in diseases such as progeria, cancer, asthma, and transplant rejection. 9 ecSOD, another copper-and zinc-containing dismutase, is a primary antioxidant enzyme secreted to the extracellular space. ecSOD is expressed highly in selected tissues, including blood vessels, heart, lungs, kidney, placenta, and extracellular fluids. ecSOD plays an important role in regulating blood pressure and vascular contraction, at least in part, through modulating the endothelial function by controlling the levels of extracellular and nitric oxide bioactivity in the vasculature. 10,11 ecSOD has also been proposed to play an important role in neurologic, pulmonary, and arthriti...

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Section: Factors Involved In the Regulation Of Ecsod Expression And Amentioning

confidence: 99%

Section: Copper and Copper Transport Pathwaysmentioning

confidence: 99%

Section: Copper and Copper Transport Pathwaysmentioning

confidence: 99%

mentioning

confidence: 99%

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Extracellular superoxide dismutase (ecSOD) in vascular biology: an update on exogenous gene transfer and endogenous regulators of ecSOD

Qin

Reszka

Fukai

et al. 2008

Translational Research

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“…A potential explanation for how angiotensin II was stimulating Cu,Zn-SOD activity without increasing expression of this protein evolved from investigating the role of copper chaperone proteins, which is the focus of recent research by Jeney et al 3 and Qin et al, 4 along with Dr Fukai, a coauthor of the article discussed in this editorial. His group has been studying how Cu chaperones participate in the regulation of Cu,Zn-SOD expression, and the influence of angiotensin II on Cu,Zn-SOD was subsequently investigated.…”

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confidence: 99%

Extracellular Superoxide Dismutase Depletion in Hypertension Unmasks a New Role for Angiotensin II in Regulating Cu,Zn-Superoxide Dismutase Activity

Wolin

2006

Hypertension

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W hile studying the effects of 2 weeks of angiotensin II infusion in extracellular superoxide dismutase knockout (ecSOD Ϫ/Ϫ ) mice on increasing superoxide and promoting hypertension, Gongora et al 1 made the surprising observation that NO production and its associated endothelium-dependent relaxation were actually improved by angiotensin II treatment in aorta from these mice without altering the expression of endothelial NO synthase. The studies were initially designed to further examine in ec-SOD Ϫ/Ϫ mice the concept that an elevation of superoxide causes a compensatory increase in the expression of ecSOD, which blunts the hypertensive response to angiotensin II and preserves endothelium-dependent vasodilatation. Evidence for this initial hypothesis was seen in measurements of blood pressure and in the response of isolated mesenteric resistance arteries. Angiotensin II treatment was observed to cause the hypothesized greater increase in blood pressure in the ec-SOD Ϫ/Ϫ mice compared with control animals and a loss of endothelium-dependent relaxation to acetylcholine, associated with the detection of increased superoxide in the resistance arteries. Endothelium-dependent relaxation to acetylcholine was impaired in the aorta of ecSOD Ϫ/Ϫ mice even in the absence of angiotensin II treatment. Thus, a dominant effect of depleted ecSOD in resistance arteries and aorta is an attenuation of endothelium-dependent relaxation, which could originate from superoxide scavenging NO and/or impairment of the conversion of superoxide to hydrogen peroxide, a potential alternative mediator of endothelium-dependent relaxation in mouse mesenteric resistance arteries. 2 The surprising observation made in the study by Gongora et al 1 was that angiotensin II-elicited impairment of endotheliumdependent relaxation seen in control mice was actually improved in aorta from the ecSOD Ϫ/Ϫ animals, associated with increased NO and decreased superoxide detection by spin trapping electron spin resonance methods and decreases in intracellular superoxide measured by dihydroethidine. The properties of superoxide generation and metabolism were investigated to elucidate how angiotensin II could be improving endothelialdependent relaxation in aorta from ecSOD Ϫ/Ϫ mice. Angiotensin II infusion increased reduced nicotinamide-adenine dinucleotide phosphate-dependent superoxide generation and the expression of Nox-1 in aorta from control and ecSOD Ϫ/Ϫ mice; however, its effects were greater in the control mice. Aorta from the ec-SOD Ϫ/Ϫ mice show normal levels of expression of cytosolic Cu,Zn-superoxide dismutase (SOD) and intramitochondrial Mn-SOD and the expected absence of ecSOD. In addition, angiotensin II treatment decreased Mn-SOD and did not alter the expression of Cu,Zn-SOD in the ecSOD Ϫ/Ϫ mice. With results like these, one might not want to continue a study of this type. However, these investigators observed that exposure of the ecSOD Ϫ/Ϫ mice to angiotensin II increased Cu,Zn-SOD activity by Ϸ2-fold, without altering its expression, an observat...

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An Overview and Update ofATP7AMutations Leading to Menkes Disease and Occipital Horn Syndrome

Tümer

2013

Human Mutation

124

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Menkes disease (MD) is a lethal multisystemic disorder of copper metabolism. Progressive neurodegeneration and connective tissue disturbances, together with the peculiar "kinky" hair, are the main manifestations. MD is inherited as an X-linked recessive trait, and as expected the vast majority of patients are males. MD occurs because of mutations in the ATP7A gene and the vast majority of ATP7A mutations are intragenic mutations or partial gene deletions. ATP7A is an energy-dependent transmembrane protein, which is involved in the delivery of copper to the secreted copper enzymes and in the export of surplus copper from cells. Severely affected MD patients die usually before the third year of life. A cure for the disease does not exist, but very early copper-histidine treatment may correct some of the neurological symptoms. This study reviews 274 published and 18 novel disease causing mutations identified in 370 unrelated MD patients, nonpathogenic variants of ATP7A, functional studies of the ATP7A mutations, and animal models of MD.

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Essential role for the Menkes ATPase in activation of extracellular superoxide dismutase: implication for vascular oxidative stress

Cited by 78 publications

References 50 publications

Extracellular superoxide dismutase (ecSOD) in vascular biology: an update on exogenous gene transfer and endogenous regulators of ecSOD

Extracellular superoxide dismutase (ecSOD) in vascular biology: an update on exogenous gene transfer and endogenous regulators of ecSOD

Extracellular Superoxide Dismutase Depletion in Hypertension Unmasks a New Role for Angiotensin II in Regulating Cu,Zn-Superoxide Dismutase Activity

An Overview and Update ofATP7AMutations Leading to Menkes Disease and Occipital Horn Syndrome

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