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Sirt1 Overexpression Inhibits Fibrous Scar Formation and Improves Functional Recovery After Cerebral Ischemic Injury Through the Deacetylation of 14–3-3ζ

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Abstract

Cerebral ischemic stroke is one of the leading causes of human death. The fibrous scar is one of major factors influencing repair in central nervous system (CNS) injury. Silencing information regulator 2-related enzyme 1 (Sirt1) can regulate peripheral tissue and organ fibrosis. However, it is unclear how the fibrous scar forms and is regulated and it is unknown whether and how Sirt1 regulates the formation of the fibrous scar after cerebral ischemic stroke. Therefore, in the present study, we examined the effects of Sirt1 on the formation of the fibrotic scar after middle cerebral artery occlusion/reperfusion (MCAO/R) injury in vivo and on the transforming growth factor β1 (TGF-β1)-induced meningeal fibroblast fibrotic response in vitro, and we explored the molecular mechanisms underlying the Sirt1-regulated fibrosis process in vitro. We found that MCAO/R injury induced fibrotic scar formation in the ischemic area, which was accompanied by the downregulation of Sirt1 expression. The overexpression of Sirt1 reduced the infarct volume, improved Nissl body structure and reduced neurons injury, attenuated formation of fibrotic scar, upregulated growth associated protein43 (GAP43) and synaptophysin (SYP) expression, and promoted neurological function recovery. Similarly, Sirt1 expression was also downregulated in the TGF-β1-induced fibrosis model. Sirt1 overexpression inhibited fibroblast migration, proliferation, transdifferentiation into myofibroblasts, and secretion of extracellular matrix(ECM) by regulating the deacetylation of lysine at K49 and K120 sites of 14–3-3ζ in vitro. Therefore, we believe that Sirt1 could regulate fibrous scar formation and improve neurological function after cerebral ischemic stroke through regulating deacetylation of 14–3-3ζ.

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Acknowledgements

We acknowledge and appreciate our colleagues for their valuable suggestions and technical assistance for this study.

Funding

This study was funded by the National Nature Science Foundation of China (Grant no. 81971229 and 82171456).

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Authors and Affiliations

  1. Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China

    Yue Chen, Jiagui Huang, Jie Liu, Huimin Zhu, Xuemei Li, Jun Wen, Mingfen Tian, Jiangxia Ren, Li Zhou & Qin Yang

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  1. Yue Chen
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Correspondence to Qin Yang.

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All experimental procedures were approved by the Ethics Committee of Chongqing Medical University.

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Highlights

1. Sirt1 expression is downregulated in the ischemic area of rats with MCAO/R injury and in the activated fibroblasts.

2. Sirt1 overexpression reduces fibrotic scar formation and improves neurological function in vivo.

3. Sirt1 overexpression inhibits the fibrotic reaction in fibroblasts in vitro through the deacetylation of 14–3-3ζ.

4. Sirt1 may be a novel therapeutic target of ischemic stroke by regulating fibrotic scarring.

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Chen, Y., Huang, J., Liu, J. et al. Sirt1 Overexpression Inhibits Fibrous Scar Formation and Improves Functional Recovery After Cerebral Ischemic Injury Through the Deacetylation of 14–3-3ζ. Mol Neurobiol 60, 4795–4810 (2023). https://doi.org/10.1007/s12035-023-03378-9

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