Abstract 15712: Sirt2 Regulates Cardiac Hypertrophic in Response to Pressure Overload
Background: Heart failure is associated with a change in cardiac energy metabolism and increased oxidative stress. Sirtuins (SIRTs) are NAD+-dependent deacetylases and critical regulators of energy metabolism and oxidative stress response. Accumulating evidence indicates that SIRT family members play different roles in cardiac remodeling in response to stress. However, the function of SIRT2, the only cytosolic protein in the family, in regulating cardiac hypertrophy is largely unknown.
Methods and results: To explore the role of SIRT2 in the development of cardiac hypertrophy, we examined the response of SIRT2-/- mice and their littermate controls to sustained pressure overload by transaortic constriction (TAC). SIRT2-/- mice displayed normal adult appearance and cardiovascular parameters at baseline. However, in response to TAC, SIRT2-/- mice displayed resistant to the pathological hypertrophic response, whereas their littermate controls developed cardiac hypertrophy and heart failure. Furthermore, SIRT2-/- mice had lower heart weight/body weight ratio, diminished wall thickness (0.96±0.074 vs 0.8±0.051mm), and sustained cardiac contractility compared to control mice. After 28 days of TAC, percentage of fractional shortening decreased to 16.47±1.78 in control mice, but remained at 26.17± 4.03 in SIRT2-/- mice. Additionally, the mRNA levels of atrial natriuretic factor (ANF) and B-type natriuretic peptide (BNP) were decreased in SIRT2-/- mice compared to wild type mice 4 weeks after TAC, indicating a stronger reduction of fetal gene expression. Finally, phospho-Akt levels were lower in SIRT2 -/- mice compared to wild type mice after TAC.
Conclusion: Our results suggest that SIRT2 plays a role in the development of heart failure after TAC and that its deletion exerts protection against cardiac dysfunction, most likely through Akt pathway.
Author Disclosures: X. Yang: None. R. Wu: None. C. Kamide: None. M. Shang: None. H. Ardehali: None.
- © 2014 by American Heart Association, Inc.