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Updated: Jul 16, 2025
Improved Rodent Model of Myocardial Ischemia and Reperfusion Injury
Published on: March 7, 2022
SIRT2 inhibition protects against cardiac hypertrophy and ischemic injury
Xiaoyan Yang1, Hsiang-Chun Chang1, Yuki Tatekoshi1
1Feinberg Cardiovascular and Renal Research Institute, Northwestern University School of Medicine, Chicago, 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.
Insights
Sirtuin 2 (SIRT2) worsens heart damage and cardiac hypertrophy. Inhibiting SIRT2 improves heart function and reduces hypertrophy, offering a new therapeutic target for heart disease.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Epigenetics
Background:
- Sirtuins (SIRTs) are NAD+-dependent enzymes involved in cellular regulation.
- The specific role of cytoplasmic sirtuin 2 (SIRT2) in cardiac stress responses remained unknown.
- Cardiac hypertrophy and ischemic injury are significant cardiovascular diseases.
Purpose of the Study:
- To investigate the role of SIRT2 in cardiac injury and hypertrophy.
- To elucidate the molecular mechanisms underlying SIRT2's function in the stressed heart.
- To evaluate SIRT2 as a potential therapeutic target for cardiac disorders.
Main Methods:
- Utilized knockout mouse models with global and cardiomyocyte-specific SIRT2 deletion.
- Assessed cardiac function following ischemia-reperfusion and pressure overload.
- Investigated the interaction between SIRT2 and nuclear factor erythroid-derived 2-like 2 (NRF2) signaling.
- Administered a specific SIRT2 inhibitor to mouse hearts.
Main Results:
- SIRT2 deletion improved cardiac function after ischemia-reperfusion and pressure overload.
- SIRT2 deficiency led to increased expression of antioxidant proteins via NRF2.
- NRF2 deletion reversed the protective effects of SIRT2 deletion.
- SIRT2 inhibition reduced cardiac size and attenuated hypertrophy.
Conclusions:
- SIRT2 plays a detrimental role in the stressed heart, promoting cardiac injury and hypertrophy.
- SIRT2 negatively regulates the NRF2 antioxidant pathway in cardiomyocytes.
- Targeting SIRT2 pharmacologically presents a novel therapeutic strategy for cardiac hypertrophy and injury.
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