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Rescue of Mitochondrial SIRT3 Ameliorates Ischemia-like Injury in Human Endothelial Cells

Structural and functional alterations of vasculature caused by age-related factors is critically involved in the pathogenesis of ischemic stroke. The longevity genes sirtuins (SIRTs) are extensively investigated in aging-associated pathologies, but their distinct roles in ischemic stroke still remai...

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Autores principales: Liu, Xi, Li, Yi, Zhang, Zhen, Lu, Juan, Pei, Gang, Huang, Shichao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9409423/
https://www.ncbi.nlm.nih.gov/pubmed/36012382
http://dx.doi.org/10.3390/ijms23169118
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author Liu, Xi
Li, Yi
Zhang, Zhen
Lu, Juan
Pei, Gang
Huang, Shichao
author_facet Liu, Xi
Li, Yi
Zhang, Zhen
Lu, Juan
Pei, Gang
Huang, Shichao
author_sort Liu, Xi
collection PubMed
description Structural and functional alterations of vasculature caused by age-related factors is critically involved in the pathogenesis of ischemic stroke. The longevity genes sirtuins (SIRTs) are extensively investigated in aging-associated pathologies, but their distinct roles in ischemic stroke still remain to be clarified. To address this question, we applied oxygen and glucose deprived/reperfusion (OGD/R) to induce ischemic injury in human endothelial cells (ECs), which are the main component of vasculature in the brain. The results showed that OGD/R led to various damages to ECs, including compromised cell viability, increased LDH release, overproduced ROS, enhanced apoptosis and caspase activity. Meanwhile, the expression of mitochondrial SIRT3 was robustly decreased in ECs after OGD/R treatment. Consistently, rescue of SIRT3 by ectopic expression, but not nuclear SIRT1, in ECs reversed the OGD/R-induced cell damage. Interestingly, some front-line drugs for ischemic stroke, including clopidogrel, aspirin and dl-3-n-butylphthalide (NBP), also rescued SIRT3 and reduced OGD/R-induced endothelial injury, suggesting that the recovery of SIRT3 expression was critical for the protection of these drugs. Moreover, our results demonstrated that 10-hydroxy-NBP (OHNBP), a major metabolite of NBP, showed better blood-brain barrier crossing capability than NBP, but still retained the effects on SIRT3 by NBP. Together, our results suggested that SIRT3 may serve as a potential novel target for treatment of ischemic stroke.
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spelling pubmed-94094232022-08-26 Rescue of Mitochondrial SIRT3 Ameliorates Ischemia-like Injury in Human Endothelial Cells Liu, Xi Li, Yi Zhang, Zhen Lu, Juan Pei, Gang Huang, Shichao Int J Mol Sci Article Structural and functional alterations of vasculature caused by age-related factors is critically involved in the pathogenesis of ischemic stroke. The longevity genes sirtuins (SIRTs) are extensively investigated in aging-associated pathologies, but their distinct roles in ischemic stroke still remain to be clarified. To address this question, we applied oxygen and glucose deprived/reperfusion (OGD/R) to induce ischemic injury in human endothelial cells (ECs), which are the main component of vasculature in the brain. The results showed that OGD/R led to various damages to ECs, including compromised cell viability, increased LDH release, overproduced ROS, enhanced apoptosis and caspase activity. Meanwhile, the expression of mitochondrial SIRT3 was robustly decreased in ECs after OGD/R treatment. Consistently, rescue of SIRT3 by ectopic expression, but not nuclear SIRT1, in ECs reversed the OGD/R-induced cell damage. Interestingly, some front-line drugs for ischemic stroke, including clopidogrel, aspirin and dl-3-n-butylphthalide (NBP), also rescued SIRT3 and reduced OGD/R-induced endothelial injury, suggesting that the recovery of SIRT3 expression was critical for the protection of these drugs. Moreover, our results demonstrated that 10-hydroxy-NBP (OHNBP), a major metabolite of NBP, showed better blood-brain barrier crossing capability than NBP, but still retained the effects on SIRT3 by NBP. Together, our results suggested that SIRT3 may serve as a potential novel target for treatment of ischemic stroke. MDPI 2022-08-14 /pmc/articles/PMC9409423/ /pubmed/36012382 http://dx.doi.org/10.3390/ijms23169118 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Liu, Xi
Li, Yi
Zhang, Zhen
Lu, Juan
Pei, Gang
Huang, Shichao
Rescue of Mitochondrial SIRT3 Ameliorates Ischemia-like Injury in Human Endothelial Cells
title Rescue of Mitochondrial SIRT3 Ameliorates Ischemia-like Injury in Human Endothelial Cells
title_full Rescue of Mitochondrial SIRT3 Ameliorates Ischemia-like Injury in Human Endothelial Cells
title_fullStr Rescue of Mitochondrial SIRT3 Ameliorates Ischemia-like Injury in Human Endothelial Cells
title_full_unstemmed Rescue of Mitochondrial SIRT3 Ameliorates Ischemia-like Injury in Human Endothelial Cells
title_short Rescue of Mitochondrial SIRT3 Ameliorates Ischemia-like Injury in Human Endothelial Cells
title_sort rescue of mitochondrial sirt3 ameliorates ischemia-like injury in human endothelial cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9409423/
https://www.ncbi.nlm.nih.gov/pubmed/36012382
http://dx.doi.org/10.3390/ijms23169118
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