Modulating Lysine Crotonylation in Cardiomyocytes Improves Myocardial Outcomes

作者：Wenqian Cai, Dacai Xu, Chui Zeng, Fan Liao, Ruiqi Li, Yingjiong Lin, Yue Zhao, Wenyan Dong, Qingwen Wang, Haili Yang, Daqiang Wen, Jianbiao Gu, Weihui Shentu, Yu H, Xiaochun Zhang, Jianrui Wei, Jinzhu Duan · 发表于：Circulation Research · 年份：2022 · DOI：10.1161/circresaha.122.321054 · 被引用次数：82 · 研究领域：Cardiac Fibrosis and Remodeling、Sirtuins and Resveratrol in Medicine、Peptidase Inhibition and Analysis

BACKGROUND: Ischemic heart disease is a major global public health challenge, and its functional outcomes remain poor. Lysine crotonylation (Kcr) was recently identified as a post-translational histone modification that robustly indicates active promoters. However, the role of Kcr in myocardial injury is unknown. In this study, we aimed to clarify the pathophysiological significance of Kcr in cardiac injury and explore the underlying mechanism. METHODS: We investigated the dynamic change of both the Kcr sites and protein level in left ventricular tissues at 2 time points following sham or cardiac ischemia-reperfusion injury, followed by liquid chromatography-coupled tandem mass tag mass spectrometry. After validation of the enriched protein Kcr by immunoprecipitation and Western blot, the function and mechanism of specific Kcr sites were further investigated in vitro and in vivo by gain- or loss-of-function mutations targeting Kcr sites of selected proteins. RESULTS: We found that cardiac ischemia-reperfusion injury triggers preferential Kcr of proteins required for cardiomyocyte contractility, including mitochondrial and cytoskeleton proteins, which occurs largely independently of protein-level changes in the same proteins. Those exhibiting Kcr changes were associated not only with disruption of cardiomyocyte mitochondrial, sarcomere architecture, and gap junction but also with cardiomyocyte autophagy and apoptosis. Modulating site-specific Kcr of selected mitochondrial prot...