SIRT2 inhibition protects against cardiac hypertrophy and ischemic injury
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eLife assessment
In this study, Yang et al. have shown that SIRT2 has adverse effects on the heart in response to injury. Further, they demonstrate that deletion of Sirt2 is protective through stabilization and increased nuclear translocation of NRF2, which leads to increased expression of antioxidant genes. They also show that pharmacological inhibition of SIRT2 protects the heart against the development of cardiac hypertrophy.
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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.
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eLife assessment
In this study, Yang et al. have shown that SIRT2 has adverse effects on the heart in response to injury. Further, they demonstrate that deletion of Sirt2 is protective through stabilization and increased nuclear translocation of NRF2, which leads to increased expression of antioxidant genes. They also show that pharmacological inhibition of SIRT2 protects the heart against the development of cardiac hypertrophy.
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Reviewer #1 (Public Review):
In this manuscript, the authors examine the role of Sirt2 on cardiac hypertrophy by using 2 in-vivo models- systemic KO of Sirt2 and cardiac-specific KO of Sirt 2. The authors show that Sirt2 is important for the development of heart failure and cardiac hypertrophy. Mechanistically, the authors show that Sirt2 regulates NRF2 and that deletion of Sirt2 is protective through stabilization and increased nuclear translocation of NRF2. The paper is clinically relevant and the data is of high quality.
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Reviewer #2 (Public Review):
In this study, Yang et al. have shown that SIRT2 plays an adverse effect on the heart in response to injury. Further, the groups showed that the deletion of Sirt2 is protective through stabilization and increased nuclear translocation of NRF2, which leads to increased expression of antioxidant genes. They also show that pharmacological inhibition of SIRT2 protects the heart against the development of cardiac hypertrophy. Although this is an interesting finding, at the same time, this study contradicts the previous findings where Xiaoqiang Tang et al. https://doi.org/10.1161/CIRCULATIONAHA.117.028728Circulation. 2017;136:2051-2067) have shown that SITR2 as a cardioprotective deacetylase and Sirt2 knockout is markedly exaggerated cardiac hypertrophy and fibrosis. Although Yang et al. in the discussion part …
Reviewer #2 (Public Review):
In this study, Yang et al. have shown that SIRT2 plays an adverse effect on the heart in response to injury. Further, the groups showed that the deletion of Sirt2 is protective through stabilization and increased nuclear translocation of NRF2, which leads to increased expression of antioxidant genes. They also show that pharmacological inhibition of SIRT2 protects the heart against the development of cardiac hypertrophy. Although this is an interesting finding, at the same time, this study contradicts the previous findings where Xiaoqiang Tang et al. https://doi.org/10.1161/CIRCULATIONAHA.117.028728Circulation. 2017;136:2051-2067) have shown that SITR2 as a cardioprotective deacetylase and Sirt2 knockout is markedly exaggerated cardiac hypertrophy and fibrosis. Although Yang et al. in the discussion part have mentioned that this could be due to mice background. In my opinion, this is not satisfactory. It is important for the scientific community to come to a conclusion about the function of SIRT2 in the heart. The author could use the Global germ-line Sirt2-KO mice (C57BL/6J background; stock no. 012772) TAC model to show the function of SITR2 in cardiac hypertrophy.
The strength of this article is the mechanism where the author showed that SIRT2 function is through the increased NRF2 deacetylation and its degradation and eventual reduction in the levels of antioxidant genes.
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