Abstract 12579: Sirt2 Contributes to the Development of Heart Failure Through a Nrf2 Dependent Pathway

Introduction: 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. However, the function of SIRT2, the only cytosolic sirtuin protein, in regulating the development of heart failure is largely unknown. Methods and results: To explore the role of SIRT2 in the development of heart failure, we examined the response of Sirt2 -/- mice and their littermate controls to pressure overload by transverse aortic constriction (TAC) and cardiac ischemia/reperfusion (I/R). Sirt2 -/- mice had normal appearance and cardiovascular parameters at baseline. However, in response to TAC, Sirt2 -/- mice displayed resistance to the pathological hypertrophic response. In the I/R injury model, Sirt2 -/- mice had better cardiac function and less cardiac fibrosis after 28 days of surgeries compared to WT mice. In vitro , Sirt2 knockdown reduced reactive oxygen species (ROS) production and cell death in neonatal rat cardiomyocytes (NRCM) after H 2 O 2 treatment. Since cellular oxidative stress is a key contributing factor to both I/R and cardiac hypertrophy, and nuclear factor (erythroid-derived 2)-like 2 (NRF2) plays a major role in antioxidant activity of the cell through regulation of several antioxidant proteins, we tested whether NRF2 is involved in SIRT2-mediated cardiac response to oxidative stress. We found that NRF2 expression is higher in NRCM with Sirt2 knockdown compared to WT cells after H 2 O 2 stimulation. And NRF2 is translocated into the nucleus and its anti-oxidant target proteins are upregulated in NRCM with Sirt2 knockdown. Further experiments demonstrated that SIRT2 directly interacts with and deacetylates NRF2, and reduces its nuclear translocation and transcriptional activity. In addition, Sirt2 -/- mice have higher levels of acetylated NRF2 in the heart. Finally, knockdown of both Sirt2 and Nrf2 abrogates the effects of Sirt2 knockdown on ROS production and cellular damage. Conclusion: Our results indicate that SIRT2 contributes to the development of heart failure in mice, and promotes oxidative stress injury in cardiomyocytes by deacetylating NRF2 and altering its activity.