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

作者：Przemek A. Gorski, Seung Pil Jang, Dongtak Jeong, Ah Young Lee, Philyoung Lee, Jae Gyun Oh, Vadim Chepurko, Dong Kwon Yang, Tae Hwan Kwak, Soo Hyun Eom, Zee‐Yong Park, Yung Joon Yoo, Do Han Kim, Hyun Kook, Yoichi Sunagawa, Tatsuya Morimoto, Koji Hasegawa, Junichi Sadoshima, Peter Vangheluwe, Roger J. Hajjar, Woo Jin Park, Changwon Kho · 发表于：Circulation Research · 年份：2019 · DOI：10.1161/circresaha.118.313865 · 被引用次数：136 · 研究领域：Sirtuins and Resveratrol in Medicine、Endoplasmic Reticulum Stress and Disease、Histone Deacetylase Inhibitors Research

RATIONALE: -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 ...