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Post-ischaemic silencing of p66Shc reduces ischaemia/reperfusion brain injury and its expression correlates to clinical outcome in stroke


Spescha, R D; Klohs, J; Semerano, A; Giacalone, G; Derungs, R S; Reiner, M F; Rodriguez Gutierrez, D; Mendez-Carmona, N; Glanzmann, M; Savarese, G; Kränkel, N; Akhmedov, A; Keller, S; Mocharla, P; Kaufmann, M R; Wenger, R H; Vogel, J; Kulic, L; Nitsch, R M; Beer, J H; Peruzzotti-Jametti, L; Sessa, Maria; Lüscher, Thomas F; Camici, G G (2015). Post-ischaemic silencing of p66Shc reduces ischaemia/reperfusion brain injury and its expression correlates to clinical outcome in stroke. European Heart Journal, 36(25):1590-1600.

Abstract

Aim: Constitutive genetic deletion of the adaptor protein p66Shc was shown to protect from ischaemia/reperfusion injury. Here, we aimed at understanding the molecular mechanisms underlying this effect in stroke and studied p66Shc gene regulation in human ischaemic stroke.
Methods and Results: Ischaemia/reperfusion brain injury was induced by performing a transient middle cerebral artery occlusion surgery on wild-type mice. After the ischaemic episode and upon reperfusion, small interfering RNA targeting p66Shc was injected intravenously. We observed that post-ischaemic p66Shc knockdown preserved blood-brain barrier integrity that resulted in improved stroke outcome, as identified by smaller lesion volumes, decreased neurological deficits, and increased survival. Experiments on primary human brain microvascular endothelial cells demonstrated that silencing of the adaptor protein p66Shc preserves claudin-5 protein levels during hypoxia/reoxygenation by reducing nicotinamide adenine dinucleotide phosphate oxidase activity and reactive oxygen species production. Further, we found that in peripheral blood monocytes of acute ischaemic stroke patients p66Shc gene expression is transiently increased and that this increase correlates with short-term neurological outcome.
Conclusion: Post-ischaemic silencing of p66Shc upon reperfusion improves stroke outcome in mice while the expression of p66Shc gene correlates with short-term outcome in patients with ischaemic stroke.

Abstract

Aim: Constitutive genetic deletion of the adaptor protein p66Shc was shown to protect from ischaemia/reperfusion injury. Here, we aimed at understanding the molecular mechanisms underlying this effect in stroke and studied p66Shc gene regulation in human ischaemic stroke.
Methods and Results: Ischaemia/reperfusion brain injury was induced by performing a transient middle cerebral artery occlusion surgery on wild-type mice. After the ischaemic episode and upon reperfusion, small interfering RNA targeting p66Shc was injected intravenously. We observed that post-ischaemic p66Shc knockdown preserved blood-brain barrier integrity that resulted in improved stroke outcome, as identified by smaller lesion volumes, decreased neurological deficits, and increased survival. Experiments on primary human brain microvascular endothelial cells demonstrated that silencing of the adaptor protein p66Shc preserves claudin-5 protein levels during hypoxia/reoxygenation by reducing nicotinamide adenine dinucleotide phosphate oxidase activity and reactive oxygen species production. Further, we found that in peripheral blood monocytes of acute ischaemic stroke patients p66Shc gene expression is transiently increased and that this increase correlates with short-term neurological outcome.
Conclusion: Post-ischaemic silencing of p66Shc upon reperfusion improves stroke outcome in mice while the expression of p66Shc gene correlates with short-term outcome in patients with ischaemic stroke.

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Contributors:Prof. Gianvito Martino from the Neuroimmunology Unit, Division of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific Institute Milan, Italy
Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > Center for Integrative Human Physiology
05 Vetsuisse Faculty > Institute of Veterinary Physiology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
04 Faculty of Medicine > Institute of Biomedical Engineering
04 Faculty of Medicine > Institute for Regenerative Medicine (IREM)
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:22 April 2015
Deposited On:05 May 2015 10:19
Last Modified:06 Aug 2018 15:23
Publisher:Oxford University Press
ISSN:0195-668X
Funders:Swiss National Science Foundation, KFSP Tumor Oxygenation of the University of Zurich, Swiss National Science Foundation (grant number 310030_147017 to G.G.C.), Swiss National Science Foundation (grant number 310030-135815 to T.F.L), Swiss National Science Foundation (grant number 136822 to J.K.), Helmut-Horten Foundation
Additional Information:Editorial comment on this article http://dx.doi.org/10.1093/eurheartj/ehv175 This is a pre-copy-editing, author-produced PDF of an article accepted for publication in European Heart Journal following peer review. The definitive publisher-authenticated version "Post-ischaemic silencing of p66Shc reduces ischaemia/reperfusion brain injury and its expression correlates to clinical outcome in stroke R.D. Spescha, J. Klohs, A. Semerano, G. Giacalone, R.S. Derungs, M.F. Reiner, D. Rodriguez Gutierrez, N. Mendez-Carmona, M. Glanzmann, G. Savarese, N. Kränkel, A. Akhmedov, S. Keller, P. Mocharla, M.R. Kaufmann, R.H. Wenger, J. Vogel, L. Kulic, R.M. Nitsch, J.H. Beer, L. Peruzzotti-Jametti, M. Sessa, T.F. Lüscher, G.G. Camici, European Heart Journal Jul 2015, 36 (25) 1590-1600; DOI: 10.1093/eurheartj/ehv140" is available online at: http://eurheartj.oxfordjournals.org/content/36/25/1590
OA Status:Green
Publisher DOI:https://doi.org/10.1093/eurheartj/ehv140
PubMed ID:25904764
Project Information:
  • : FunderSNSF
  • : Grant ID
  • : Project TitleSwiss National Science Foundation
  • : Funder
  • : Grant ID
  • : Project TitleKFSP Tumor Oxygenation of the University of Zurich
  • : FunderSNSF
  • : Grant ID
  • : Project TitleSwiss National Science Foundation (grant number 310030_147017 to G.G.C.)
  • : FunderSNSF
  • : Grant ID
  • : Project TitleSwiss National Science Foundation (grant number 310030-135815 to T.F.L)
  • : FunderSNSF
  • : Grant ID
  • : Project TitleSwiss National Science Foundation (grant number 136822 to J.K.)
  • : Funder
  • : Grant ID
  • : Project TitleHelmut-Horten Foundation

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