Endothelial SIRT6 blunts stroke size and neurological deficit by preserving blood–brain barrier integrity: a translational study
- 11 October 2019
- journal article
- research article
- Published by Oxford University Press (OUP) in European Heart Journal
- Vol. 41 (16), 1575-1587
- https://doi.org/10.1093/eurheartj/ehz712
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.Funding Information
- Swiss Heart Foundation
- Swiss National Science Foundation (310030_175546, 310030-165990, 310030_166576)
- 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
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