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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Blood-Brain Barrier
Stroke
Endothelial Cells
Middle Cerebral Artery Infarction
Caspase 3
Brain
Cell Hypoxia
Reperfusion Injury
Knockout Mice
Brain Injuries
Genes
Reperfusion
Therapeutics
Ischemia
Survival
Mortality

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Endothelial SIRT6 blunts stroke size and neurological deficit by preserving blood-brain barrier integrity : a translational study. / Liberale, Luca; Gaul, Daniel S; Akhmedov, Alexander; Bonetti, Nicole R; Nageswaran, Vanasa; Costantino, Sarah; Pahla, Jürgen; Weber, Julien; Fehr, Vera; Vdovenko, Daria; Semerano, Aurora; Giacalone, Giacomo; Kullak-Ublick, Gerd A; Sessa, Maria; Eriksson, Urs; Paneni, Francesco; Ruschitzka, Frank; Montecucco, Fabrizio; Beer, Jürg H; Lüscher, Thomas F; Matter, Christian M; Camici, Giovanni G.

In: European Heart Journal, 11.10.2019.

Research output: Contribution to journalArticle

Liberale, L, Gaul, DS, Akhmedov, A, Bonetti, NR, Nageswaran, V, Costantino, S, Pahla, J, Weber, J, Fehr, V, Vdovenko, D, Semerano, A, Giacalone, G, Kullak-Ublick, GA, Sessa, M, Eriksson, U, Paneni, F, Ruschitzka, F, Montecucco, F, Beer, JH, Lüscher, TF, Matter, CM & Camici, GG 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
Liberale, Luca ; Gaul, Daniel S ; Akhmedov, Alexander ; Bonetti, Nicole R ; Nageswaran, Vanasa ; Costantino, Sarah ; Pahla, Jürgen ; Weber, Julien ; Fehr, Vera ; Vdovenko, Daria ; Semerano, Aurora ; Giacalone, Giacomo ; Kullak-Ublick, Gerd A ; Sessa, Maria ; Eriksson, Urs ; Paneni, Francesco ; Ruschitzka, Frank ; Montecucco, Fabrizio ; Beer, Jürg H ; Lüscher, Thomas F ; Matter, Christian M ; Camici, Giovanni G. / Endothelial SIRT6 blunts stroke size and neurological deficit by preserving blood-brain barrier integrity : a translational study. In: European Heart Journal. 2019.
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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.",
author = "Luca Liberale and Gaul, {Daniel S} and Alexander Akhmedov and Bonetti, {Nicole R} and Vanasa Nageswaran and Sarah Costantino and J{\"u}rgen Pahla and Julien Weber and Vera Fehr and Daria Vdovenko and Aurora Semerano and Giacomo Giacalone and Kullak-Ublick, {Gerd A} and Maria Sessa and Urs Eriksson and Francesco Paneni and Frank Ruschitzka and Fabrizio Montecucco and Beer, {J{\"u}rg H} and L{\"u}scher, {Thomas F} and Matter, {Christian M} and Camici, {Giovanni G}",
note = "Published on behalf of the European Society of Cardiology. All rights reserved. {\circledC} The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.",
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T1 - Endothelial SIRT6 blunts stroke size and neurological deficit by preserving blood-brain barrier integrity

T2 - a translational study

AU - Liberale, Luca

AU - Gaul, Daniel S

AU - Akhmedov, Alexander

AU - Bonetti, Nicole R

AU - Nageswaran, Vanasa

AU - Costantino, Sarah

AU - Pahla, Jürgen

AU - Weber, Julien

AU - Fehr, Vera

AU - Vdovenko, Daria

AU - Semerano, Aurora

AU - Giacalone, Giacomo

AU - Kullak-Ublick, Gerd A

AU - Sessa, Maria

AU - Eriksson, Urs

AU - Paneni, Francesco

AU - Ruschitzka, Frank

AU - Montecucco, Fabrizio

AU - Beer, Jürg H

AU - Lüscher, Thomas F

AU - Matter, Christian M

AU - Camici, Giovanni G

N1 - Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.

PY - 2019/10/11

Y1 - 2019/10/11

N2 - 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.

AB - 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.

U2 - 10.1093/eurheartj/ehz712

DO - 10.1093/eurheartj/ehz712

M3 - Article

C2 - 31603194

JO - European Heart Journal

JF - European Heart Journal

SN - 0195-668X

ER -