{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:43:04Z","timestamp":1790718184133,"version":"4.1.0"},"reference-count":61,"publisher":"Oxford University Press (OUP)","issue":"16","license":[{"start":{"date-parts":[[2019,10,11]],"date-time":"2019-10-11T00:00:00Z","timestamp":1570752000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100004362","name":"Swiss Heart Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004362","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["310030_175546"],"award-info":[{"award-number":["310030_175546"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["310030-165990"],"award-info":[{"award-number":["310030-165990"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["310030_166576"],"award-info":[{"award-number":["310030_166576"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Alfred and Annemarie von Sick Grants for Translational and Clinical Research Cardiology and Oncology"},{"name":"University Research Priority Program Integrative Human Physiology"},{"DOI":"10.13039\/501100006447","name":"University of Zurich","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006447","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Foundation for Cardiovascular Research\u2013Zurich Heart House"},{"name":"Sheikh Khalifa's Foundation Assistant Professorship"},{"name":"Faculty of Medicine, University of Zurich"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,4,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Aging is an established risk factor for stroke; genes regulating longevity are implicated in the pathogenesis of ischaemic stroke where to date, therapeutic options remain limited. The blood\u2013brain barrier (BBB) is crucially involved in ischaemia\/reperfusion (I\/R) brain injury thus representing an attractive target for developing novel therapeutic agents. Given the role of endothelial cells in the BBB, we hypothesized that the endothelial-specific expression of the recently described longevity gene SIRT6 may exhibit protective properties in stroke.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>SIRT6 endothelial expression was reduced following stroke. Endothelial-specific Sirt6 knockout (eSirt6\u2212\/\u2212) mice, as well as animals in which Sirt6 overexpression was post-ischaemically induced, underwent transient middle cerebral artery occlusion (tMCAO). eSirt6\u2212\/\u2212 animals displayed increased infarct volumes, mortality, and neurological deficit after tMCAO, as compared to control littermates. Conversely, post-ischaemic Sirt6 overexpression decreased infarct size and neurological deficit. Analysis of ischaemic brain sections revealed increased BBB damage and endothelial expression of cleaved caspase-3 in eSIRT6\u2212\/\u2212 mice as compared to controls. In primary human brain microvascular endothelial cells (HBMVECs), hypoxia\/reoxygenation (H\/R) reduced SIRT6 expression and SIRT6 silencing impaired the barrier function (transendothelial resistance) similar to what was observed in mice exposed to I\/R. Further, SIRT6-silenced HBMVECs exposed to H\/R showed reduced viability, increased cleaved caspase-3 expression and reduced activation of the survival pathway Akt. In ischaemic stroke patients, SIRT6 expression was higher in those with short-term neurological improvement as assessed by NIHSS scale and correlated with stroke outcome.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Endothelial SIRT6 exerts a protective role in ischaemic stroke by blunting I\/R-mediated BBB damage and thus, it may represent an interesting novel therapeutic target to be explored in future clinical investigation.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/eurheartj\/ehz712","type":"journal-article","created":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T19:27:38Z","timestamp":1569958058000},"page":"1575-1587","source":"Crossref","is-referenced-by-count":81,"title":["Endothelial SIRT6 blunts stroke size and neurological deficit by preserving blood\u2013brain barrier integrity: a translational study"],"prefix":"10.1093","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1472-7975","authenticated-orcid":false,"given":"Luca","family":"Liberale","sequence":"first","affiliation":[{"name":"Center for Molecular Cardiology, Schlieren Campus, University of Zurich , Wagistrasse 12, Schlieren 8952, Switzerland"},{"name":"First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa , 6 viale Benedetto XV, Genoa 16132, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel S","family":"Gaul","sequence":"additional","affiliation":[{"name":"Center for Molecular Cardiology, Schlieren Campus, University of Zurich , Wagistrasse 12, Schlieren 8952, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Akhmedov","sequence":"additional","affiliation":[{"name":"Center for Molecular Cardiology, Schlieren Campus, University of Zurich , Wagistrasse 12, Schlieren 8952, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole R","family":"Bonetti","sequence":"additional","affiliation":[{"name":"Center for Molecular Cardiology, Schlieren Campus, University of Zurich , Wagistrasse 12, Schlieren 8952, Switzerland"},{"name":"Department of Internal Medicine, Cantonal Hospital of Baden , Im Ergel 1, Baden 5404, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanasa","family":"Nageswaran","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Charit\u00e9-Universit\u00e4tsmedizin Berlin , Campus Benjamin Franklin, Hindenburgdamm 30, Berlin 12203, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Costantino","sequence":"additional","affiliation":[{"name":"Center for Molecular Cardiology, Schlieren Campus, University of Zurich , Wagistrasse 12, Schlieren 8952, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen","family":"Pahla","sequence":"additional","affiliation":[{"name":"Center for Molecular Cardiology, Schlieren Campus, University of Zurich , Wagistrasse 12, Schlieren 8952, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Weber","sequence":"additional","affiliation":[{"name":"Institute of Molecular Life Sciences, University of Zurich , Winterthurerstrasse 190, Zurich 8057, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Fehr","sequence":"additional","affiliation":[{"name":"Center for Molecular Cardiology, Schlieren Campus, University of Zurich , Wagistrasse 12, Schlieren 8952, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1236-3290","authenticated-orcid":false,"given":"Daria","family":"Vdovenko","sequence":"additional","affiliation":[{"name":"Center for Molecular Cardiology, Schlieren Campus, University of Zurich , Wagistrasse 12, Schlieren 8952, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1882-0747","authenticated-orcid":false,"given":"Aurora","family":"Semerano","sequence":"additional","affiliation":[{"name":"Department of Neurology, San Raffaele Scientific Institute , via Olgettina 60, Milano 20132, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8834-4267","authenticated-orcid":false,"given":"Giacomo","family":"Giacalone","sequence":"additional","affiliation":[{"name":"Department of Neurology, San Raffaele Scientific Institute , via Olgettina 60, Milano 20132, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerd A","family":"Kullak-Ublick","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Toxicology, University Hospital Zurich , Zurich, 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Hospital Zurich , R\u00e4mistrasse 100, Zurich 8092, Switzerland"},{"name":"Department of Research and Education, University Hospital Zurich , R\u00e4mistrasse 100, Zurich 8092, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Ruschitzka","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Heart Center, University Hospital Zurich , R\u00e4mistrasse 100, Zurich 8092, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0823-8729","authenticated-orcid":false,"given":"Fabrizio","family":"Montecucco","sequence":"additional","affiliation":[{"name":"IRCCS Ospedale Policlinico San Martino Genoa \u2013 Italian Cardiovascular Network , L.go R. Benzi 10, Genoa 16132, Italy"},{"name":"First Clinic of Internal Medicine, Department of Internal Medicine, Centre of Excellence for Biomedical Research (CEBR), University of Genoa , 6 viale Benedetto XV, Genoa 16132, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrg H","family":"Beer","sequence":"additional","affiliation":[{"name":"Center for Molecular Cardiology, Schlieren Campus, University of Zurich , Wagistrasse 12, Schlieren 8952, Switzerland"},{"name":"Department of Internal Medicine, Cantonal Hospital of Baden , Im Ergel 1, Baden 5404, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas F","family":"L\u00fcscher","sequence":"additional","affiliation":[{"name":"Center for Molecular Cardiology, Schlieren Campus, University of Zurich , Wagistrasse 12, Schlieren 8952, Switzerland"},{"name":"Royal Brompton and Harefield Hospitals, Imperial College , Dovehouse Street, London SW3 6LY, 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