SIRT2 inhibition protects against cardiac hypertrophy and ischemic injury
- Northwestern University, United States
Abstract
Sirtuins (SIRT) exhibit deacetylation or ADP-ribosyltransferase activity and regulate a wide range of cellular processes in the nucleus, mitochondria and cytoplasm. The role of the only sirtuin that resides in the cytoplasm, SIRT2, in the development of ischemic injury and cardiac hypertrophy is not known. In this paper, we show that the hearts of mice with deletion of Sirt2 (Sirt2-/-) display improved cardiac function after ischemia-reperfusion (I/R) and pressure overload (PO), suggesting that SIRT2 exerts maladaptive effects in the heart in response to stress. Similar results were obtained in mice with cardiomyocyte-specific Sirt2 deletion. Mechanistic studies suggest that SIRT2 modulates cellular levels and activity of nuclear factor (erythroid-derived 2)-like 2 (NRF2), which results in reduced expression of antioxidant proteins. Deletion of Nrf2 in the hearts of Sirt2-/- mice reversed protection after PO. Finally, treatment of mouse hearts with a specific SIRT2 inhibitor reduced cardiac size and attenuates cardiac hypertrophy in response to PO. These data indicate that SIRT2 has detrimental effects in the heart and plays a role in cardiac response to injury and the progression of cardiac hypertrophy, which makes this protein a unique member of the SIRT family. Additionally, our studies provide a novel approach for treatment of cardiac hypertrophy and injury by targeting SIRT2 pharmacologically, providing a novel avenue for the treatment of these disorders.
Data availability
Source Data files are provided.
Article and author information
Author details
Jason Solomon Shapiro
Funding
NIH Office of the Director (NIH R01 HL140973,R01 HL138982,R01 HL140927,R01 HL155953)
- Hossein Ardehali
Leducq (Cardiooncology Network)
- Hossein Ardehali
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animals were maintained and handled in accordance with the Northwestern Animal Care and Use Committee. All animal studies were approved by the Institutional Animal Care and Use Committee at Northwestern University (Chicago, Illinois) and were performed in accordance with guidelines from the National Institutes of Health. The approval number of the animal protocol currently associated with this activity is IS00006808.
Copyright
© 2023, Yang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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SIRT2 inhibition protects against cardiac hypertrophy and ischemic injury
eLife 12:e85571.
https://doi.org/10.7554/eLife.85571
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