한빛사 논문
Przemek A. Gorski1,*, Seung Pil Jang2,*, Dongtak Jeong1,*, Ahyoung Lee1, Philyoung Lee1, JaeGyun Oh1, Vadim Chepurko1, Dong Kwon Yang2, Tae Hwan Kwak3, Soo Hyun Eom2, Zee-Yong Park2, Yung Joon Yoo2, Do Han Kim2, Hyun Kook4, Yoichi Sunagawa5, Tatsuya Morimoto5, Koji Hasegawa6, Junichi Sadoshima7, Roger J. Hajjar1, Woo Jin Park2,**, and Changwon Kho1,**
1Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
2College of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea
3 BethphaGen, Inc, Gwangju, Korea
4Basic Research Laboratory, Chonnam National University Medical School, Hwasun-gun, Jeollanam-do, Korea
5Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
6Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, Kyoto, Japan
7Department of Cell Biology & Molecular Medicine, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, Newark, New Jersey 07103, USA
* Authors contributed equally
**Corresponding authors:
Changwon Kho, PhD, Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, Leon and Norma Hess Center for Science and Medicine, 1470 Madison Avenue, 7th Floor, Box 1030, New York, NY 10029, USA.
Woo Jin Park, PhD, College of Life Sciences, Gwangju Institute of Science and Technology, 123 Cheomdangwagi-ro, Buk-gu, Gwangju 61005, Korea.
Abstract
Rationale: SERCA2a, sarco-endoplasmic reticulum Ca2+-ATPase, is a critical determinant of cardiac function. Reduced level and activity of SERCA2a are major features of heart failure (HF). 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 (PTM) with small ubiquitin-like modifier 1 (SUMO1). However, the roles of other PTMs 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 HF.
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, a class III histone deacetylase. Down-regulation 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, 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 HF.
Keywords : acetylation, post-translational modification
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