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001-es BibID:BIBFORM023031
Első szerző:Jeney Viktória (vegyész, kémia tanár)
Cím:Role of Antioxidant-1 in Extracellular Superoxide Dismutase Function and Expression / Viktoria Jeney, Shinichi Itoh, Maria Wendt, Quinton Gradek, Masuko Ushio-Fukai, David G. Harrison, Tohru Fukai
Dátum:2005
ISSN:0009-7330
Megjegyzések:The extracellular superoxide dismutase (ecSOD or SOD3) is a copper-containing enzyme which is highly expressed in the vasculature. Copper-containing enzymes require copper chaperones for their activity however the chaperone which delivers copper to SOD3 has not previously been defined. Atox1 is a copper chaperone proposed to deliver copper to the trans-Golgi network. Because SOD3 is secreted via the trans-Golgi network, we sought to determine whether Atox1 acts as a copper chaperone for SOD3. Using recombinant human SOD3, we found that the specific activity of SOD3 directly correlates with its copper content (R-2 = 0.99). SOD3 specific activity in the conditioned medium from cultured Atox1(-/-) fibroblasts was markedly decreased, but could be recovered to that of wild-type cells by copper addition. These results indicated that Atox1 is required for delivering copper to SOD3 for its full activity. Unexpectedly, the protein and mRNA levels of SOD3 were dramatically decreased in cultured Atox1(-/-) fibroblasts. This was associated with a marked decrease in SOD3 transcription rate but no change in SOD3 mRNA stability. Overexpression of Atox1 markedly increased SOD3 mRNA in both Atox1(-/-) and Atox1(-/-) cells. These findings indicate that Atox1 positively regulates SOD3 transcription. Because SOD3 protein is upregulated in atherosclerotic vessels, we examined expression of Atox1 in vessels from ApoE(-/-) mice. Western and immunohistochemical analysis in ApoE(-/-) mice revealed that both Atox1 and SOD3 protein levels are markedly increased in atherosclerotic intimal lesions. In summary, Atox1 functions not only as a copper chaperone for SOD3 but also as a positive regulator for SOD3 transcription and may have an important role in modulating oxidative stress in the cardiovascular system.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Circulation Research. - 96 : 7 (2005), p. 723-729. -
További szerzők:Itoh, Shinichi Wendt, Maria Gradek, Quinton Ushio-Fukai, Masuko Harrison, David G. Fukai, Tohru
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001-es BibID:BIBFORM023034
Első szerző:Nguyen, Andrew D.
Cím:Fibulin-5 Is a Novel Binding Protein for Extracellular Superoxide Dismutase / Andrew D. Nguyen, Shinichi Itoh, Viktoria Jeney, Hiromi Yanagisawa, Mitsuaki Fujimoto, Masuko Ushio-Fukai, Tohru Fukai
Dátum:2004
ISSN:0009-7330
Megjegyzések:The extracellular superoxide dismutase (ecSOD) plays an important role in atherosclerosis and endothelial function by modulating levels of the superoxide anion (O-2(.-)) in the extracellular space. Although heparan sulfate proteoglycan is an important ligand for ecSOD, little is known about other biological binding partners of ecSOD. The goal of this study was to identify novel proteins that interact with ecSOD. A yeast two-hybrid screening of a human aorta cDNA library using ecSOD as bait identified fibulin-5 as a predominant binding protein for ecSOD. Further analysis showed that the binding domain of ecSOD within fibulin-5 mapped to its C-terminal domain. In vitro pulldown assays and coimmunoprecipitation analysis further confirmed that ecSOD interacts with fibulin-5 in vitro and in vivo. Studies using fibulin-5(-/-) mice indicated that fibulin-5 is required for binding of ecSOD to vascular tissue. Importantly, the decrease in tissue-bound ecSOD levels in aortas from fibulin-5(-/-) mice was associated with an increase in vascular O-2(.-) levels. Furthermore, immunohistochemical analysis using ApoE(-/-) mice suggested a codistribution of ecSOD and fibulin-5 in atherosclerotic vessels. In summary, we provide in this study the first evidence that the ecSOD-fibulin-5 interaction is required for ecSOD binding to vascular tissues, thereby regulating vascular O-2(.-) levels. This interaction may represent a novel mechanism for controlling vascular redox state in the extracellular space in various cardiovascular diseases such as atherosclerosis and hypertension in which oxidative stress is increased.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Circulation Research. - 95 : 11 (2004), p. 1067-1074. -
További szerzők:Itoh, Shinichi Jeney Viktória (1971-) (vegyész, kémia tanár) Yanagisawa, Hiromi Fujimoto, Mitsuaki Ushio-Fukai, Masuko Fukai, Tohru
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3.

001-es BibID:BIBFORM023027
Első szerző:Qin, Zhenyu
Cím:Essential role for the Menkes ATPase in activation of extracellular superoxide dismutase : implication for vascular oxidative stress / Qin Z., Itoh S., Jeney V., Ushio-Fukai M., Fukai T.
Dátum:2006
ISSN:0892-6638
Megjegyzések:Extracellular superoxide dismutase (SOD3), a secretory copper enzyme, plays an important role in atherosclerosis and hypertension by modulating the levels of extracellular superoxide anion (O2*-) in the vasculature. Little is known about the mechanisms by which SOD3 obtains its catalytic copper cofactor. Menkes ATPase (MNK) has been shown to transport cytosolic copper to the secretory pathway in nonvascular cells. We performed the present study to determine whether MNK is required for the activation of SOD3 in the vasculature. Here we show that MNK was highly expressed in the various vascular tissues and cells. Aortas and cultured fibroblasts from MNK mutant (MNK(mut)) mice showed a marked decrease in specific activity of SOD3, but not SOD1 (cytosolic form), which was partially restored by copper addition. Copper treatment in wild-type cells promoted the direct interaction and colocalization of SOD3 with MNK in the trans-Golgi network (TGN), suggesting that MNK transports copper to SOD3 in the TGN. Aortas of MNK(mut) mice revealed a decrease in activity of SOD3, but not SOD1, in association with a robust increase in O2*- levels. Finally, both MNK and SOD3 proteins were highly expressed in the intimal lesions of atherosclerotic vessels. In conclusion, vascular MNK plays an essential role in full activity of SOD3 through transporting copper to SOD3 in the TGN, thereby regulating O2*- levels in the vasculature. These studies provide a novel insight into vascular MNK as a critical modulator of "superoxide" stress, which may contribute to cardiovascular disease.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:Faseb Journal. - 20 : 2 (2006), p. 334-336. -
További szerzők:Itoh, Shinichi Jeney Viktória (1971-) (vegyész, kémia tanár) Ushio-Fukai, Masuko Fukai, Tohru
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