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Cardioprotective effects of thioredoxin in myocardial ischemia and reperfusion: role of S-nitrosation [corrected]

Cardioprotective effects of thioredoxin in myocardial ischemia and reperfusion: role of S-nitrosation [corrected]
Cardioprotective effects of thioredoxin in myocardial ischemia and reperfusion: role of S-nitrosation [corrected]
Apoptosis contributes to myocardial ischemia/reperfusion (MI/R) injury, and both thioredoxin (Trx) and nitric oxide have been shown to exert antiapoptotic effects in vitro. Recent evidence suggests that this particular action of Trx requires S-nitrosation at Cys-69. The present study sought to investigate whether or not exogenously applied Trx reduces MI/R injury in vivo and to which extent this effect depends on S-nitrosation. Adult mice were subjected to 30 min of MI and treated with either vehicle or human Trx (hTrx, 2 mg/kg, i.p.) 10 min before reperfusion. Native hTrx was incorporated into myocardial tissue as shown by immunostaining, and reduced MI/R injury as evidenced by decreased terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining, DNA fragmentation, caspase-3 activity, and infarct size. When hTrx was partially S-nitrosated by preincubation with S-nitrosoglutathione, its cardioprotective effect was markedly enhanced. Treatment with hTrx significantly reduced p38 mitogen-activated protein kinase (MAPK) activity, and this effect was also potentiated by S-nitrosation. To further address the role of S-nitrosation for the overall antiapoptotic effect to Trx, the action of Escherichia coli Trx (eTrx) was investigated in the same model. Whereas eTrx inhibited MI/R-induced apoptosis to a degree similar to hTrx, S-nitrosation of this protein, which lacks Cys-69, failed to further enhance its antiapoptotic action. Collectively, our results demonstrate that systemically applied Trx is taken up by the myocardium to exert potent cardioprotective effects in vivo, offering interesting therapeutic avenues. In the case of hTrx, these effects are further potentiated by S-nitrosation, but this posttranslational modification is not essential for protection.
reperfusion injury, apoptosis, antioxidant, posttranslational regulation
0027-8424
11471-11476
Tao, Ling
67443fe5-e99d-46f8-8a9c-6fa0ca1b69a4
Gao, Erhe
42801b15-d02c-4972-832d-95dd99fa410c
Bryan, Nathan S.
709ff51c-c864-4862-9e3f-c5cfd3961025
Qu, Yan
7806f542-3124-4a7e-a9b0-2d4dedd3db17
Liu, Hui-Rong
caf83bd0-3704-4116-b5ef-52a0cbcf1749
Hu, Aihua
9f045892-7f00-4f85-b8f5-935419b9bb69
Christopher, Theodore A.
c40e3333-0c1e-4e1b-9365-87ecbbec3c44
Lopez, Bernard L.
5a036013-f58c-493c-9961-09495903abc9
Yodoi, Junji
457c749f-ec34-4920-b01a-282f527796f9
Koch, Walter J
db9a3929-7e95-419d-a320-15e11f68d9e3
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Ma, Xin L.
a93586fc-e73f-4c5d-bc20-a54337ea4950
Tao, Ling
67443fe5-e99d-46f8-8a9c-6fa0ca1b69a4
Gao, Erhe
42801b15-d02c-4972-832d-95dd99fa410c
Bryan, Nathan S.
709ff51c-c864-4862-9e3f-c5cfd3961025
Qu, Yan
7806f542-3124-4a7e-a9b0-2d4dedd3db17
Liu, Hui-Rong
caf83bd0-3704-4116-b5ef-52a0cbcf1749
Hu, Aihua
9f045892-7f00-4f85-b8f5-935419b9bb69
Christopher, Theodore A.
c40e3333-0c1e-4e1b-9365-87ecbbec3c44
Lopez, Bernard L.
5a036013-f58c-493c-9961-09495903abc9
Yodoi, Junji
457c749f-ec34-4920-b01a-282f527796f9
Koch, Walter J
db9a3929-7e95-419d-a320-15e11f68d9e3
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Ma, Xin L.
a93586fc-e73f-4c5d-bc20-a54337ea4950

Tao, Ling, Gao, Erhe, Bryan, Nathan S., Qu, Yan, Liu, Hui-Rong, Hu, Aihua, Christopher, Theodore A., Lopez, Bernard L., Yodoi, Junji, Koch, Walter J, Feelisch, Martin and Ma, Xin L. (2004) Cardioprotective effects of thioredoxin in myocardial ischemia and reperfusion: role of S-nitrosation [corrected]. Proceedings of the National Academy of Sciences, 101 (31), 11471-11476. (doi:10.1073/pnas.0402941101). (PMID:15277664)

Record type: Article

Abstract

Apoptosis contributes to myocardial ischemia/reperfusion (MI/R) injury, and both thioredoxin (Trx) and nitric oxide have been shown to exert antiapoptotic effects in vitro. Recent evidence suggests that this particular action of Trx requires S-nitrosation at Cys-69. The present study sought to investigate whether or not exogenously applied Trx reduces MI/R injury in vivo and to which extent this effect depends on S-nitrosation. Adult mice were subjected to 30 min of MI and treated with either vehicle or human Trx (hTrx, 2 mg/kg, i.p.) 10 min before reperfusion. Native hTrx was incorporated into myocardial tissue as shown by immunostaining, and reduced MI/R injury as evidenced by decreased terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining, DNA fragmentation, caspase-3 activity, and infarct size. When hTrx was partially S-nitrosated by preincubation with S-nitrosoglutathione, its cardioprotective effect was markedly enhanced. Treatment with hTrx significantly reduced p38 mitogen-activated protein kinase (MAPK) activity, and this effect was also potentiated by S-nitrosation. To further address the role of S-nitrosation for the overall antiapoptotic effect to Trx, the action of Escherichia coli Trx (eTrx) was investigated in the same model. Whereas eTrx inhibited MI/R-induced apoptosis to a degree similar to hTrx, S-nitrosation of this protein, which lacks Cys-69, failed to further enhance its antiapoptotic action. Collectively, our results demonstrate that systemically applied Trx is taken up by the myocardium to exert potent cardioprotective effects in vivo, offering interesting therapeutic avenues. In the case of hTrx, these effects are further potentiated by S-nitrosation, but this posttranslational modification is not essential for protection.

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e-pub ahead of print date: 26 July 2004
Published date: 3 August 2004
Keywords: reperfusion injury, apoptosis, antioxidant, posttranslational regulation
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 337844
URI: https://eprints.soton.ac.uk/id/eprint/337844
ISSN: 0027-8424
PURE UUID: 15c05cbb-ba66-4f5a-84f9-8fd016068f93
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

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Date deposited: 22 Jun 2012 09:02
Last modified: 06 Jun 2018 12:29

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Contributors

Author: Ling Tao
Author: Erhe Gao
Author: Nathan S. Bryan
Author: Yan Qu
Author: Hui-Rong Liu
Author: Aihua Hu
Author: Theodore A. Christopher
Author: Bernard L. Lopez
Author: Junji Yodoi
Author: Walter J Koch
Author: Martin Feelisch ORCID iD
Author: Xin L. Ma

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