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

Luca Liberale, Daniel S Gaul, Alexander Akhmedov, Nicole R Bonetti, Vanasa Nageswaran, Sarah Costantino, Jürgen Pahla, Julien Weber, Vera Fehr, Daria Vdovenko, Aurora Semerano, Giacomo Giacalone, Gerd A Kullak-Ublick, Maria Sessa, Urs Eriksson, Francesco Paneni, Frank Ruschitzka, Fabrizio Montecucco, Jürg H Beer, Thomas F LüscherChristian M Matter, Giovanni G Camici

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalEuropean Heart Journal
DOIs
Publication statusE-pub ahead of print - Oct 11 2019

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    Liberale, L., Gaul, D. S., Akhmedov, A., Bonetti, N. R., Nageswaran, V., Costantino, S., Pahla, J., Weber, J., Fehr, V., Vdovenko, D., Semerano, A., Giacalone, G., Kullak-Ublick, G. A., Sessa, M., Eriksson, U., Paneni, F., Ruschitzka, F., Montecucco, F., Beer, J. H., ... Camici, G. G. (2019). Endothelial SIRT6 blunts stroke size and neurological deficit by preserving blood-brain barrier integrity: a translational study. European Heart Journal. https://doi.org/10.1093/eurheartj/ehz712