Endothelial SIRT6 blunts stroke size and neurological deficit by preserving blood–brain barrier integrity: a translational study
| Autor: | Fabrizio Montecucco, Thomas F. Lüscher, Luca Liberale, Daniel S. Gaul, Giacomo Giacalone, Daria Vdovenko, Sarah Costantino, Julien Weber, Jürgen Pahla, Urs Eriksson, Maria Sessa, Giovanni G. Camici, Vanasa Nageswaran, Vera Fehr, Gerd A. Kullak-Ublick, Alexander Akhmedov, Aurora Semerano, Frank Ruschitzka, Christian M. Matter, Jürg H. Beer, Nicole R. Bonetti, Francesco Paneni |
|---|---|
| Přispěvatelé: | University of Zurich, Camici, Giovanni G |
| Rok vydání: | 2019 |
| Předmět: |
Cell death
medicine.medical_specialty Endothelium Ischemia 610 Medicine & health 030204 cardiovascular system & hematology Blood–brain barrier Neuroprotection 2705 Cardiology and Cardiovascular Medicine Brain Ischemia 11459 Center for Molecular Cardiology Brain ischemia Mice 03 medical and health sciences 0302 clinical medicine Internal medicine Sirtuin 6 SIRT6 Animals Humans Sirtuins Medicine Middle cerebral artery occlusion Stroke 030304 developmental biology 0303 health sciences business.industry Endothelial Cells Infarction Middle Cerebral Artery Human brain Ischaemia/reperfusion Hypoxia (medical) medicine.disease Mice Inbred C57BL medicine.anatomical_structure Endocrinology Blood-Brain Barrier 10199 Clinic for Clinical Pharmacology and Toxicology 10209 Clinic for Cardiology medicine.symptom Cardiology and Cardiovascular Medicine business |
| Zdroj: | European Heart Journal. 41:1575-1587 |
| ISSN: | 1522-9645 0195-668X |
| DOI: | 10.1093/eurheartj/ehz712 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|