R D Spescha1, J Klohs2, A Semerano3, G Giacalone3, R S Derungs4, M F Reiner1, D Rodriguez Gutierrez5, N Mendez-Carmona5, M Glanzmann1, G Savarese1, N Kränkel6, A Akhmedov1, S Keller1, P Mocharla1, M R Kaufmann7, R H Wenger7, J Vogel8, L Kulic4, R M Nitsch4, J H Beer9, L Peruzzotti-Jametti3, M Sessa3, T F Lüscher10, G G Camici11. 1. Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Schlieren CH-8952, Switzerland Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland. 2. Institute for Biomedical Engineering, Swiss Federal Institute of Technology Zurich (ETHZ), Zurich, Switzerland. 3. Department of Neurology, San Raffaele Scientific Institute, Milan, Italy. 4. Division of Psychiatry Research, University of Zurich, Schlieren, Switzerland. 5. Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Schlieren CH-8952, Switzerland. 6. Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Schlieren CH-8952, Switzerland Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland Department of Cardiology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany. 7. Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland Institute of Physiology, University of Zurich, Zurich, Switzerland. 8. Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland. 9. Department of Internal Medicine, Cantonal Hospital of Baden, Baden, Switzerland. 10. Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Schlieren CH-8952, Switzerland Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland Cardiology, University Heart Center, University Hospital, Zurich, Switzerland. 11. Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, Schlieren CH-8952, Switzerland Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland giovanni.camici@uzh.ch giovannicamici@hotmail.com.
Abstract
AIM: Constitutive genetic deletion of the adaptor protein p66(Shc) was shown to protect from ischaemia/reperfusion injury. Here, we aimed at understanding the molecular mechanisms underlying this effect in stroke and studied p66(Shc) 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 p66(Shc) was injected intravenously. We observed that post-ischaemic p66(Shc) 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 p66(Shc) 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 p66(Shc) gene expression is transiently increased and that this increase correlates with short-term neurological outcome. CONCLUSION: Post-ischaemic silencing of p66(Shc) upon reperfusion improves stroke outcome in mice while the expression of p66(Shc) gene correlates with short-term outcome in patients with ischaemic stroke. Published on behalf of the European Society of Cardiology. All rights reserved.
AIM: Constitutive genetic deletion of the adaptor protein p66(Shc) was shown to protect from ischaemia/reperfusion injury. Here, we aimed at understanding the molecular mechanisms underlying this effect in stroke and studied p66(Shc) gene regulation in humanischaemic 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 p66(Shc) was injected intravenously. We observed that post-ischaemic p66(Shc) 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 p66(Shc) 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 strokepatientsp66(Shc) gene expression is transiently increased and that this increase correlates with short-term neurological outcome. CONCLUSION: Post-ischaemic silencing of p66(Shc) upon reperfusion improves stroke outcome in mice while the expression of p66(Shc) gene correlates with short-term outcome in patients with ischaemic stroke. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Steven J Forrester; Daniel S Kikuchi; Marina S Hernandes; Qian Xu; Kathy K Griendling Journal: Circ Res Date: 2018-03-16 Impact factor: 17.367
Authors: Alexander Akhmedov; Nicole R Bonetti; Martin F Reiner; Remo D Spescha; Heidi Amstalden; Mario Merlini; Daniel S Gaul; Candela Diaz-Cañestro; Sylvie Briand-Schumacher; Rebecca S Spescha; Aurora Semerano; Giacomo Giacalone; Gianluigi Savarese; Fabrizio Montecucco; Luka Kulic; Roger M Nitsch; Christian M Matter; Gerd A Kullak-Ublick; Maria Sessa; Thomas F Lüscher; Jürg H Beer; Luca Liberale; Giovanni G Camici Journal: J Cereb Blood Flow Metab Date: 2018-08-03 Impact factor: 6.200
Authors: Catherine M Davis; Wenri H Zhang; Elyse M Allen; Thierno M Bah; Robert E Shangraw; Nabil J Alkayed Journal: Int J Mol Sci Date: 2021-05-21 Impact factor: 5.923