Endothelial SIRT6 blunts stroke size and neurological deficit by preserving blood–brain barrier integrity: a translational study

Author:

Liberale Luca12ORCID,Gaul Daniel S1,Akhmedov Alexander1,Bonetti Nicole R13,Nageswaran Vanasa4,Costantino Sarah1,Pahla Jürgen1,Weber Julien5,Fehr Vera1,Vdovenko Daria1ORCID,Semerano Aurora6ORCID,Giacalone Giacomo6ORCID,Kullak-Ublick Gerd A7,Sessa Maria6ORCID,Eriksson Urs18,Paneni Francesco1910,Ruschitzka Frank9,Montecucco Fabrizio1112ORCID,Beer Jürg H13,Lüscher Thomas F113,Matter Christian M19ORCID,Camici Giovanni G191014ORCID

Affiliation:

1. Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, Schlieren 8952, Switzerland

2. First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, Genoa 16132, Italy

3. Department of Internal Medicine, Cantonal Hospital of Baden, Im Ergel 1, Baden 5404, Switzerland

4. Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin 12203, Germany

5. Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, Zurich 8057, Switzerland

6. Department of Neurology, San Raffaele Scientific Institute, via Olgettina 60, Milano 20132, Italy

7. Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland

8. GZO Spital Wetzikon, Spitalstrasse 66, Wetzikon 8620, Switzerland

9. Department of Cardiology, University Heart Center, University Hospital Zurich, Rämistrasse 100, Zurich 8092, Switzerland

10. Department of Research and Education, University Hospital Zurich, Rämistrasse 100, Zurich 8092, Switzerland

11. IRCCS Ospedale Policlinico San Martino Genoa – Italian Cardiovascular Network, L.go R. Benzi 10, Genoa 16132, Italy

12. 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

13. Royal Brompton and Harefield Hospitals, Imperial College, Dovehouse Street, London SW3 6LY, UK

14. Zurich Neuroscience Center, University of Zurich, Winterthurerstrasse 190, Zurich 8057, Switzerland

Abstract

Abstract Aims 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–brain 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. Methods and results SIRT6 endothelial expression was reduced following stroke. Endothelial-specific Sirt6 knockout (eSirt6−/−) mice, as well as animals in which Sirt6 overexpression was post-ischaemically induced, underwent transient middle cerebral artery occlusion (tMCAO). eSirt6−/− 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−/− 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. Conclusion 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.

Funder

Swiss Heart Foundation

Swiss National Science Foundation

Alfred and Annemarie von Sick Grants for Translational and Clinical Research Cardiology and Oncology

University Research Priority Program Integrative Human Physiology

University of Zurich

Foundation for Cardiovascular Research–Zurich Heart House

Sheikh Khalifa's Foundation Assistant Professorship

Faculty of Medicine, University of Zurich

Publisher

Oxford University Press (OUP)

Subject

Cardiology and Cardiovascular Medicine

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