Role of SIRT1 in Modulating Acetylation of the Sarco-Endoplasmic Reticulum Ca ²⁺ -ATPase in Heart Failure

Abstract

Rationale: SERCA2a, sarco-endoplasmic reticulum Ca 2+ -ATPase, is a critical determinant of cardiac function. Reduced level and activity of SERCA2a are major features of heart failure. Accordingly, intensive efforts have been made to develop efficient modalities for SERCA2a activation. We showed that the activity of SERCA2a is enhanced by post-translational modification with SUMO1 (small ubiquitin-like modifier 1). However, the roles of other post-translational modifications on SERCA2a are still unknown. Objective: In this study, we aim to assess the role of lysine acetylation on SERCA2a function and determine whether inhibition of lysine acetylation can improve cardiac function in the setting of heart failure. Methods and Results: The acetylation of SERCA2a was significantly increased in failing hearts of humans, mice, and pigs, which is associated with the reduced level of SIRT1 (sirtuin 1), a class III histone deacetylase. Downregulation of SIRT1 increased the SERCA2a acetylation, which in turn led to SERCA2a dysfunction and cardiac defects at baseline. In contrast, pharmacological activation of SIRT1 reduced the SERCA2a acetylation, which was accompanied by recovery of SERCA2a function and cardiac defects in failing hearts. Lysine 492 (K492) was of critical importance for the regulation of SERCA2a activity via acetylation. Acetylation at K492 significantly reduced the SERCA2a activity, presumably through interfering with the binding of ATP to SERCA2a. In failing hearts, acetylation at K492 appeared to be mediated by p300 (histone acetyltransferase p300), a histone acetyltransferase. Conclusions: These results indicate that acetylation/deacetylation at K492, which is regulated by SIRT1 and p300, is critical for the regulation of SERCA2a activity in hearts. Pharmacological activation of SIRT1 can restore SERCA2a activity through deacetylation at K492. These findings might provide a novel strategy for the treatment of heart failure.

Acetylation of SERCA2a, Another Target for Heart Failure Treatment?

“…In the current issue of Circulation Research 8 the role of acetylation of SERCA2a in HF is reported for the first time. In contrast to the stimulatory effects of glutathionylation on C674 7 and SUMOylation on K480 and K585 2 on SERCA2a activity, Gorski et al 8 demonstrate that acetylation of K492 decreases both SERCA2a activity and myocyte contractility. Furthermore, they discovered that the acetylation of K492 was increased in failing human tissue and pressure-overloaded mouse hearts, which was due to decreased sirtuin 1 (SIRT1).…”

Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure

“… 19–21 Conversely, SIRT1 enrichment or activation improves cardiac function and prevents adverse ventricular remodelling following experimental infarction 22 , 23 ; mitigates cardiac injury and mitochondrial dysfunction produced by diverse cellular stresses 24–26 ; and ameliorates fibrosis produced by pressure overload. 27 In experimental models of heart failure, activation of SIRT1 restores the functionality of sarco-endoplasmic reticulum Ca 2+ -ATPase and improves cardiac function, 28 , 29 whereas suppression of SIRT1 decreases angiogenesis and leads to systolic and diastolic abnormalities. 19 , 21 , 30 …”

Targeting Ca2 + Handling Proteins for the Treatment of Heart Failure and Arrhythmias

“…However, more recent data suggests direct post-transcriptional modifications of SERCA2a contribute to its decreased activity (Kranias and Hajjar, 2012). In HF, SERCA2 can undergo either 'stimulatory' modification by glutathionylation on C674 (Adachi et al, 2004) and/or SUMOylation on K480 and K585 (Kho et al, 2011), and 'inhibitory' acetylation of K492 (Gorski et al, 2019). These modifications to SERCA2a and its regulatory proteins provides more scope for enhancing SERCA2 activity in HF patients.…”