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Deletion of the ageing gene p66Shc reduces early stroke size following ischaemia/reperfusion brain injury

Spescha, Remo D. ; Shi, Yi ; Wegener, Susanne ; Keller, Stephan ; Weber, Bruno ; Wyss, Matthias M. ; Lauinger, Nadine ; Tabatabai, Ghazaleh ; Paneni, Francesco ; Cosentino, Francesco ; Hock, Christoph ; Weller, Michael ; Nitsch, Roger M. ; Lüscher, Thomas F. ; Camici, Giovanni G.

In: European Heart Journal, 2013, vol. 34, no. 2, p. 96-103

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    Titre
    • Deletion of the ageing gene p66Shc reduces early stroke size following ischaemia/reperfusion brain injury
    Auteur
    • Spescha, Remo D.. Cardiovascular Research, Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    • Shi, Yi. Cardiovascular Research, Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    • Wegener, Susanne. Department of Neurology, University Hospital Zurich, Zurich, Switzerland
    • Keller, Stephan. Cardiovascular Research, Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    • Weber, Bruno. Institute of Pharmacology and Toxicology, University of Zurich, Zürich, Switzerland
    • Wyss, Matthias M.. Institute of Pharmacology and Toxicology, University of Zurich, Zürich, Switzerland
    • Lauinger, Nadine. Department of Neurology, University Hospital Zurich, Zurich, Switzerland
    • Tabatabai, Ghazaleh. Department of Neurology, University Hospital Zurich, Zurich, Switzerland
    • Paneni, Francesco. Cardiovascular Research, Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    • Cosentino, Francesco. Cardiovascular Research, Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    • Hock, Christoph. Division of Psychiatry Research, University of Zurich, Zurich, Switzerland
    • Weller, Michael. Department of Neurology, University Hospital Zurich, Zurich, Switzerland
    • Nitsch, Roger M.. Division of Psychiatry Research, University of Zurich, Zurich, Switzerland
    • Lüscher, Thomas F.. Cardiovascular Research, Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    • Camici, Giovanni G.. Cardiovascular Research, Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
    Type de document
    • Postprint
    Langue
    • Inglese
    Publié dans
    • European Heart Journal, 2013, vol. 34, no. 2, p. 96-103. Oxford University Press
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:297614
    Summary
    Aims Stroke is a leading cause of morbidity and mortality, and its incidence increases with age. Both in animals and in humans, oxidative stress appears to play an important role in ischaemic stroke, with or without reperfusion. The adaptor protein p66Shc is a key regulator of reactive oxygen species (ROS) production and a mediator of ischaemia/reperfusion damage in ex vivo hearts. Hence, we hypothesized that p66Shc may be involved in ischaemia/reperfusion brain damage. To this end, we investigated whether genetic deletion of p66Shc protects from ischaemia/reperfusion brain injury. Methods and results Transient middle cerebral artery occlusion (MCAO) was performed to induce ischaemia/reperfusion brain injury in wild-type (Wt) and p66Shc knockout mice (p66Shc−/−), followed by 24 h of reperfusion. Cerebral blood flow and blood pressure measurements revealed comparable haemodynamics in both experimental groups. Neuronal nuclear antigen immunohistochemical staining showed a significantly reduced stroke size in p66Shc−/− when compared with Wt mice (P < 0.05, n = 7-8). In line with this, p66Shc−/− mice exhibited a less impaired neurological function and a decreased production of free radicals locally and systemically (P < 0.05, n = 4-5). Following MCAO, protein levels of gp91phox nicotinamide adenine dinucleotide phosphate oxidase subunit were increased in brain homogenates of Wt (P < 0.05, n = 4), but not of p66Shc−/− mice. Further, reperfusion injury in Wt mice induced p66Shc protein in the basilar and middle cerebral artery, but not in brain tissue, suggesting a predominant involvement of vascular p66Shc. Conclusion In the present study, we show that the deletion of the ageing gene p66Shc protects mice from ischaemia/reperfusion brain injury through a blunted production of free radicals. The ROS mediator p66Shc may represent a novel therapeutical target for the treatment of ischaemic stroke