Abstract
Sirtuin 3 (Sirt3) is a member of the Sirtuin family proteins and known to regulate multiple physiological processes such as metabolism and aging. As stroke is an aging-related disease, in this work, we attempt to examine the role and potential mechanism of Sirt3 in regulating ischemic stroke by using a permanent middle cerebral artery occlusion (pMCAO) model in wild type (WT) and Sirt3 knockout (KO) mice, coupled with oxygen glucose deprivation (OGD) experiments in cultured primary astrocytes. Sirt3 deficiency aggravated neuronal cell apoptosis and neurological deficits after brain ischemia. In addition, Sirt3 KO mice showed more severe blood–brain barrier (BBB) disruption and inflammatory responses compared with WT group in the acute phase. Furthermore, specific overexpression of Sirt3 in astrocytes by injecting glial fibrillary acidic protein (GFAP)::Sirt3 virus in ischemic region showed protective effect against stroke-induced damage. Mechanistically, Sirt3 could regulate vascular endothelial growth factor (VEGF) expression by inhibiting hypoxia inducible factor-1α (HIF-1α) signaling after ischemia (OGD). Our results have shown that Sirt3 plays a protective role in ischemic stroke via regulating HIF-1α/VEGF signaling in astrocytes, and reversal of the Sirt3 expression at the acute phase could be a worthy direction for stroke therapy.
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Abbreviations
- MCAO:
-
Middle cerebral artery occlusion
- WT:
-
Wild type
- KO:
-
Knockout
- mNSS:
-
Modified neurological severity scores
- GFAP:
-
Glial fibrillary acidic protein
- VEGF:
-
Vascular endothelial growth factor
- TUNEL:
-
TdT-mediated dUTP nick-end labeling
- HIF-1:
-
Hypoxia inducible element-1
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Acknowledgements
This study was supported by Grants from National Key Grant (2016YFC0906400), Ministry of Science and Technology (2013CB945604), National Natural Science Foundation, China (31270032), and SJTU Funding (YG2017MS52).
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WX conceived the project and drafted and revised the manuscript. XY designed experiments, analyzed the data, and drafted the manuscript. YZ, KG, and KY performed experiments. JS assisted in the experimental design. All authors read and approved the final manuscript.
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Animal procedures were performed according to a protocol approved by the Institutional Animal Care and Use Committee (ACUC), Shanghai Jiao Tong University, Shanghai, China. The specific protocol number approved by ACUC was 2017032.
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Yang, X., Zhang, Y., Geng, K. et al. Sirt3 Protects Against Ischemic Stroke Injury by Regulating HIF-1α/VEGF Signaling and Blood–Brain Barrier Integrity. Cell Mol Neurobiol 41, 1203–1215 (2021). https://doi.org/10.1007/s10571-020-00889-0
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DOI: https://doi.org/10.1007/s10571-020-00889-0