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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2012

Open Access 01-12-2012 | Research

SOD1 aggregation in astrocytes following ischemia/reperfusion injury: a role of NO-mediated S-nitrosylation of protein disulfide isomerase (PDI)

Authors: Xueping Chen, Teng Guan, Chen Li, Huifang Shang, Liying Cui, Xin-Min Li, Jiming Kong

Published in: Journal of Neuroinflammation | Issue 1/2012

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Abstract

Background

Ubiquitinated-protein aggregates are implicated in cerebral ischemia/reperfusion injury. The very presence of these ubiquitinated-protein aggregates is abnormal and seems to be disease-related. However, it is not clear what leads to aggregate formation and whether the aggregations represent a reaction to aggregate-mediated neurodegeneration.

Methods

To study the nitrosative stress-induced protein aggregation in cerebral ischemia/reperfusion injury, we used primary astrocyte cultures as a cell model, and systematically examined their iNOS expression and consequent NO generation following oxygen glucose deprivation and reperfusion. The expression of protein disulfide isomerase (PDI) and copper-zinc superoxide dismutase (SOD1) were also examined, and the biochemical interaction between PDI and SOD1 was determined by immunoprecipitation. In addition, the levels of S-nitrosylated PDI in cultured astrocytes after oxygen glucose deprivation and reperfusion treatment were measured using the biotin-switch assay. The formation of ubiquitinated-protein aggregates was detected by immunoblot and immunofluorescence staining.

Results

Our data showed that the up-regulation of iNOS expression after oxygen glucose deprivation and reperfusion treatment led to excessive NO generation. Up-regulation of PDI and SOD1 was also identified in cultured astrocytes following oxygen glucose deprivation and reperfusion, and these two proteins were found to bind to each other. Furthermore, the increased nitrosative stress due to ischemia/reperfusion injury was highly associated with NO-induced S-nitrosylation of PDI, and this S-nitrosylation of PDI was correlated with the formation of ubiquitinated-protein aggregates; the levels of S-nitrosylated PDI increased in parallel with the formation of aggregates. When NO generation was pharmacologically inhibited by iNOS specific inhibitor 1400W, S-nitrosylation of PDI was significantly blocked. In addition, the formation of ubiquitinated-protein aggregates in cultured astrocytes following oxygen glucose deprivation and reperfusion was also suppressed by 1400W. Interestingly, these aggregates were colocalized with SOD1, which was found to co-immunoprecipitate with PDI.

Conclusions

NO-mediated S-nitrosylation of PDI may be involved in the formation of the SOD1-linked ubiquitinated-protein aggregates in cerebral ischemia/reperfusion injury.
Literature
1.
Farkas O, Povlishock JT: Cellular and subcellular change evoked by diffuse traumatic brain injury: a complex web of change extending far beyond focal damage. Prog Brain Res 2007, 161:43–59.CrossRefPubMed
2.
3.
Shih AY, Johnson DA, Wong G, Kraft AD, Jiang L, Erb H, Johnson JA, Murphy TH: Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci 2003, 23:3394–406.PubMed
4.
Sagara JI, Miura K, Bannai S: Maintenance of neuronal glutathione by glial cells. J Neurochem 1993, 61:1672–1676.CrossRefPubMed
5.
Cherian L, Goodman JC, Robertson CS: Brain nitric oxide changes after controlled cortical impact injury in rats. J Neurophysiol 2000, 83:2171–2178.PubMed
6.
Murphy S: Production of nitric oxide by glial cells: regulation and potential roles in the CNS. Glia 2000, 29:1–13.CrossRefPubMed
7.
Iadecola C, Zhang F, Casey R, Nagayama M, Ross ME: Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J Neurosci 1997, 17:9157–64.PubMed
8.
Loihl AK, Whalen S, Campbell IL, Mudgett JS, Murphy S: Transcriptional activation following cerebral ischemia in mice of a promoter-deleted nitric oxide synthase-2 gene. J Biol Chem 1999, 274:8844–9.CrossRefPubMed
9.
10.
Lerouet D, Beray-Berthat V, Palmier B, Plotkine M, Margaill I: Changes in oxidative stress, iNOS activity and neutrophil infiltration in severe transient focal cerebral ischemia in rats. Brain Res 2002, 958:166–75.CrossRefPubMed
11.
Zhu D-Y, Deng Q, Yao H-H, Wang D-C, Deng Y, Liu G-Q: Inducible nitric oxide synthase expression in the ischemic core and penumbra after transient focal cerebral ischemia in mice. Life Sci 2002, 71:1985–96.CrossRefPubMed
12.
13.
DeGracia DJ, Hu BR: Irreversible translation arrest in the reperfused brain. J Cereb Blood F Met 2007, 27:875–93.
14.
Giffard RG, Xu L, Zhao H, Carrico W, Ouyang Y, Qiao Y, Sapolsky R, Steinberg G, Hu B, Yenari MA: Chaperones, protein aggregation, and brain protection from hypoxic/ischemic injury. J Exp Biol 2004, 207:3213–20.CrossRefPubMed
15.
Groenendyk J, Michalak M: Endoplasmic reticulum quality control and apoptosis. Acta Biochim Pol 2005, 52:381–95.PubMed
16.
17.
Lyles MM, Gilbert HF: Catalysis of the oxidative folding of ribonuclease A by protein disulfide isomerase: dependence of the rate on the composition of the redox buffer. Biochemistry 1991, 30:613–19.CrossRefPubMed
18.
Atkin JD, Farg MA, Turner BJ, Tomas D, Lysaght JA, Nunan J, Rembach A, Nagley P, Beart PM, Cheema SS, Horne MK: Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1. J Biol Chem 2006, 281:30152–65.CrossRefPubMed
19.
Hetz C, Russelakis-Carneiro M, Walchli S, Carboni S, Vial-Knecht E, Maundrell K, Castilla J, Soto C: The disulfide isomerase Grp58 is a protective factor against prion neurotoxicity. J Neurosci 2005, 25:2793–802.CrossRefPubMed
20.
Ko HS, Uehara T, Nomura Y: Role of ubiquilin associated with protein-disulfide isomerase in the endoplasmic reticulum in stress-induced apoptotic cell death. J Biol Chem 2002, 277:35386–92.CrossRefPubMed
21.
Uehara T, Nakamura T, Yao D, Shi Z-Q, Gu Z, Ma Y, Masliah E, Nomura Y, Lipton SA: S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature 2006, 441:513–17.CrossRefPubMed
22.
Hess DT, Matsumoto A, Kim S-O, Marshall HE, Stamler JS: Protein S-nitrosylation: purview and parameters. Nat Rev Mol Cell Biol 2005, 6:150–66.CrossRefPubMed
23.
Hu J, Castets F, Guevara JL, Van Eldik LJ: S100 beta stimulates inducible nitric oxide synthase activity and mRNA levels in rat cortical astrocytes. J Biol Chem 1996, 271:2543–7.CrossRefPubMed
24.
Beck J, Lenart B, Kintner DB, Sun D: Na-K-Cl cotransporter contributes to glutamate-mediated excitotoxicity. J Neurosci 2003, 23:5061–8.PubMed
25.
Lee J, Ryu H, Ferrante RJ, Morris SM Jr: Ratan RR: Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox. Proc Natl Acad Sci USA 2003, 100:4843–8.CrossRefPubMedPubMedCentral
26.
Walker AK, Farg MA, Bye CR, McLean CA, Horne MK, Atkin JD: Protein disulphide isomerase protects against protein aggregation and is S-nitrosylated in amyotrophic lateral sclerosis. Brain 2010, 133:105–16.CrossRefPubMed
27.
Chen X, Kintner DB, Baba A, Matsuda T, Shull GE, Sun D: Protein aggregation in neurons following OGD: a role for Na + and Ca 2+ ionic dysregulation. J Neurochem 2010, 112:173–82.CrossRefPubMed
28.
Jaffrey SR, Erdjument-Bromage H, Ferris CD, Tempst P, Snyder SH: Protein S-nitrosylation: a physiological signal for neuronal nitric oxide. Nat Cell Biol 2001, 3:193–7.CrossRefPubMed
29.
30.
31.
Rothwell NJ, Relton JK: Involvement of cytokines in acute neurodegeneration in the CNS. Neurosci Biobehav Rev 1993, 17:217–27.CrossRefPubMed
32.
Galea E, Feinstein DL, Reis DJ: Induction of calcium-independent nitric oxide synthase activity in primary rat glial cultures. Proc Natl Acad Sci USA 1992, 89:10945–9.CrossRefPubMedPubMedCentral
33.
Simmons ML, Murphy S: Cytokines regulate L-arginine-dependent cyclic GMP production in rat glial cells. Eur J Neurosci 1993, 5:825–31.CrossRefPubMed
34.
Simmons ML, Murphy S: Induction of nitric oxide synthase in glial cells. J Neurochem 1992, 59:897–905.CrossRefPubMed
35.
Schroeter M, Kury P, Jander S: Inflammatory gene expression in focal cortical brain ischemia: differences between rats and mice. Mol Brain Res 2003, 117:1–7.CrossRefPubMed
36.
Lopez-Figueroa MO, Day HE, Lee S, Rivier C, Akil H, Watson SJ: Temporal and anatomical distribution of nitric oxide synthase mRNA expression and nitric oxide production during central nervous system inflammation. Brain Res 2000, 852:239–46.CrossRefPubMed
37.
Matrone C, Pignataro G, Molinaro P, Irace C, Scorziello A, Di Renzo GF, Annunziato L: HIF-1α reveals a binding activity to the promoter of iNOS gene after permanent middle cerebral artery occlusion. J Neurochem 2004, 90:368–78.CrossRefPubMed
38.
Moro MA, Cardenas A, Hurtado O, Leza JC, Lizasoain I: Role of nitric oxide after brain ischaemia. Cell Calcium 2004, 36:265–75.CrossRefPubMed
39.
Noiva R: Protein disulfide isomerase: the multifunctional redox chaperone of the endoplasmic reticulum. Semin Cell Dev Biol 1999, 10:481–93.CrossRefPubMed
40.
Lee S-O, Cho K, Cho S, Kim I, Oh C, Ahn K: Protein disulphide isomerase is required for signal peptide peptidase-mediated protein degradation. EMBO J 2010, 29:363–75.CrossRefPubMed
41.
42.
Tanaka S, Uehara T, Nomura Y: Up-regulation of protein-disulfide isomerase in response to hypoxia/brain ischemia and its protective effect against apoptotic cell death. J Biol Chem 2000, 275:10388–93.CrossRefPubMed
43.
Severino A, Campioni M, Straino S, Salloum FN, Schmidt N, Herbrand U, Frede S, Toietta G, Di Rocco G, Bussani R, Silvestri F, Piro M, Liuzzo G, Biasucci LM, Mellone P, Feroce F, Capogrossi M, Baldi F, Fandrey J, Ehrmann M, Crea F, Abbate A, Baldi A: Identification of protein disulfide isomerase as a cardiomyocyte survival factor in ischemic cardiomyopathy. J Am Coll Cardiol 2007, 50:1029–37.CrossRefPubMed
44.
Hu BR, Janelidze S, Ginsberg MD, Busto R, Perez-Pinzon M, Sick TJ, Siesjo BK, Liu CL: Protein aggregation after focal brain ischemia and reperfusion. J Cerebr Blood F Met 2001, 21:865–75.CrossRef
45.
46.
Hu BR, Martone ME, Jones YZ, Liu CL: Protein aggregation after transient cerebral ischemia. J Neurosci 2000, 20:3191–9.PubMed
47.
48.
DeGracia DJ, Rudolph J, Roberts GG, Rafols JA, Wang J: Convergence of stress granules and protein aggregates in hippocampal cornu ammonis 1 at later reperfusion following global brain ischemia. Neuroscience 2007, 146:562–72.CrossRefPubMedPubMedCentral
49.
Zhang K, Kaufman RJ: The unfolded protein response: a stress signaling pathway critical for health and disease. Neurology 2006, 66:S102-S109.CrossRefPubMed
50.
Xu W, Liu L, Charles IG, Moncada S: Nitric oxide induces coupling of mitochondrial signalling with the endoplasmic reticulum stress response. Nat Cell Biol 2004, 6:1129–34.CrossRefPubMed
51.
Gotoh T, Mori M: Nitric oxide and endoplasmic reticulum stress. Arterioscler Thromb Vasc Biol 2006, 26:1439–46.CrossRefPubMed
52.
He J, Kang H, Yan F, Chen C: The endoplasmic reticulum-related events in S-nitrosoglutathione-induced neurotoxicity in cerebellar granule cells. Brain Res 2004, 1015:25–33.CrossRefPubMed
53.
Chung RS, Penkowa M, Dittmann J, King CE, Bartlett C, Asmussen JW, Hidalgo J, Carrasco J, Leung YKJ, Walker AK, Fung SJ, Dunlop SA, Fitzgerald M, Beazley LD, Chuah MI, Vickers JC, West AK: Redefining the role of metallothionein within the injured brain: extracellular metallothioneins play an important role in the astrocyte-neuron response to injury. J Biol Chem 2008, 283:15349–58.CrossRefPubMedPubMedCentral
54.
Leung YKJ, Pankhurst M, Dunlop SA, Ray S, Dittmann J, Eaton ED, Palumaa P, Sillard R, Chuah MI, West AK, Chung RS: Metallothionein induces a regenerative reactive astrocyte phenotype via JAK/STAT and RhoA signalling pathways. Exp Neurol 2010, 221:98–106.CrossRefPubMed
55.
Tsuru-Aoyagi K, Potts MB, Trivedi A, Pfankuch T, Raber J, Wendland M, Claus CP, Koh S-E, Ferriero D, Noble-Haeusslein LJ: Glutathione peroxidase activity modulates recovery in the injured immature brain. Ann Neurol 2009, 65:540–9.CrossRefPubMedPubMedCentral
56.
Sugawara T, Chan PH: Reactive oxygen radicals and pathogenesis of neuronal death after cerebral ischemia. Antioxid Redox Signal 2003, 5:597–607.CrossRefPubMed
57.
Wilson JX: Antioxidant defense of the brain: a role for astrocytes. Can J Physiol Pharmacol 1997, 75:1149–63.CrossRefPubMed
58.
Chan PH, Kawase M, Murakami K, Chen SF, Li Y, Calagui B, Reola L, Carlson E, Epstein CJ: Overexpression of SOD1 in transgenic rats protects vulnerable neurons against ischemic damage after global cerebral ischemia and reperfusion. J Neurosci 1998, 18:8292–9.PubMed
59.
Pineda JA, Aono M, Sheng H, Lynch J, Wellons JC, Laskowitz DT, Pearlstein RD, Bowler R, Crapo J, Warner DS: Extracellular superoxide dismutase overexpression improves behavioral outcome from closed head injury in the mouse. J Neurotrauma 2001, 18:625–34.CrossRefPubMed
60.
Zemlyak I, Nimon V, Brooke S, Moore T, McLaughlin J, Sapolsky R: Gene therapy in the nervous system with superoxide dismutase. Brain Res 2006, 1088:12–18.CrossRefPubMed
61.
Toldo S, Severino A, Abbate A, Baldi A: The role of PDI as a survival factor in cardiomyocyte ischemia. Methods Enzymol 2011, 489:47–65.CrossRefPubMed
62.
Honjo Y, Kaneko S, Ito H, Horibe T, Nagashima M, Nakamura M, Fujita K, Takahashi R, Kusaka H, Kawakami K: Protein disulfide isomerase-immunopositive inclusions in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2011, 12:444–50.CrossRefPubMed
63.
Zheng Q, Li J, Wang X: Interplay between the ubiquitin-proteasome system and autophagy in proteinopathies. Int J Physiol Pathophysiol Pharmacol 2009, 1:127–42.PubMedPubMedCentral
Metadata
Title
SOD1 aggregation in astrocytes following ischemia/reperfusion injury: a role of NO-mediated S-nitrosylation of protein disulfide isomerase (PDI)
Authors
Xueping Chen
Teng Guan
Chen Li
Huifang Shang
Liying Cui
Xin-Min Li
Jiming Kong
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-9-237

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