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Evaluation of the Neuroprotective Effect of Sirt3 in Experimental Stroke

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Abstract

Sirtuins (Sirt) are a family of NAD+ dependent histone deacetylase (HDAC) proteins implicated in aging, cell cycle regulation, and metabolism. These proteins are involved in the epigenetic modification of neuromodulatory proteins after strokevia acetylation/deacetylation. The specific role of Sirt3, a mitochondrial sirtuin, in post-stroke injury has been relatively unexplored. Using male Sirt3 knockout (KO) mice and wild-type littermates (WT), we show that Sirt3 KO mice show significant neuroprotection at 3 days after ischemia/reperfusion (I/R) or stroke injury. The deacetylation activity of Sirt3, measured as the amount of reduced acetylated lysine, was increased after stroke. Stroke-induced increases in liver kinase 1 (LKB1) activity were also reduced in KO mice at 3 days after stroke. On further investigation, we found that the levels of Sirt1, another important member of the Sirtuin family, were increased in the brains of Sirt3 KO mice after stroke. To determine the translational relevance of these findings, we then tested the effects of pharmacological inhibition of Sirt3. We found no benefit of Sirt3 inhibition despite clear evidence of deacetylation. Overall, these data suggest that Sirt3 KO mice show neuroprotection by a compensatory rise in Sirt1 rather than the loss of Sirt3 after stroke. Further analysis reveals that the beneficial effects of Sirt1 might be mediated by a decrease in LKB1 activity after stroke. Finally, our data clearly demonstrate the importance of using both pharmacological and genetic methods in pre-clinical stroke studies.

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Funding

This work was supported by National Institutes of Health grants R01NSO77769 (to Louise D McCullough) and an AHA postdoctoral fellowship 14POST20380612 (to Rajkumar Verma).

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Authors and Affiliations

  1. Department of Neurosciences, UConn Health, Farmington, CT, 06032, USA

    Rajkumar Verma, Rodney M. Ritzel, Joshua Crapser, Brett D. Friedler & Louise D. McCullough

  2. Department of Neurology, University of Texas Health Science Center, Houston, TX, 77030, USA

    Louise D. McCullough

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  1. Rajkumar Verma
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  2. Rodney M. Ritzel
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Correspondence to Rajkumar Verma.

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The authors declare that they have no conflict of interest.

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All animal protocols were approved by the University’s Institutional Animal Care and Use Committee at UConn Health, Farmington, CT, and were performed in accordance with National Institutes of Health guidelines.

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Verma, R., Ritzel, R.M., Crapser, J. et al. Evaluation of the Neuroprotective Effect of Sirt3 in Experimental Stroke. Transl. Stroke Res. 10, 57–66 (2019). https://doi.org/10.1007/s12975-017-0603-x

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  • DOI: https://doi.org/10.1007/s12975-017-0603-x

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