Endothelial SIRT6 blunts stroke size and neurological deficit by preserving blood-brain barrier integrity: A translational study: European Heart Journal

L. Liberale, D.S. Gaul, A. Akhmedov, N.R. Bonetti, V. Nageswaran, S. Costantino, J. Pahla, J. Weber, V. Fehr, D. Vdovenko, A. Semerano, Giacomo Giacalone, G.A. Kullak-Ublick, M. Sessa, U. Eriksson, F. Paneni, F. Ruschitzka, F. Montecucco, J.H. Beer, T.F. LüscherC.M. Matter, G.G. Camici

Research output: Contribution to journalArticlepeer-review


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. © 2019 Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.
Original languageEnglish
Pages (from-to)1575-1587
Number of pages13
JournalEur. Heart J.
Issue number16
Publication statusPublished - 2020


  • Cell death
  • Ischaemia/reperfusion
  • Middle cerebral artery occlusion
  • SIRT6
  • Sirtuin 6
  • Stroke
  • caspase 3
  • oxygen
  • protein kinase B
  • sirtuin 6
  • adult
  • aged
  • animal cell
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • blood brain barrier
  • brain capillary endothelial cell
  • brain hypoxia
  • brain infarction size
  • brain ischemia
  • cell survival
  • cell viability
  • clinical article
  • controlled study
  • correlation analysis
  • endothelium cell
  • enzyme activation
  • female
  • gene overexpression
  • gene silencing
  • human
  • human cell
  • knockout mouse
  • male
  • middle aged
  • middle cerebral artery occlusion
  • mortality
  • mouse
  • National Institutes of Health Stroke Scale
  • neurologic disease
  • neuroprotection
  • nonhuman
  • priority journal
  • protein cleavage
  • protein expression
  • reoxygenation
  • very elderly


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