PMID- 37245426 OWN - NLM STAT- MEDLINE DCOM- 20230619 LR - 20231120 IS - 1879-1484 (Electronic) IS - 0021-9150 (Linking) VI - 375 DP - 2023 Jun TI - Exercise-induced endothelial Mecp2 lactylation suppresses atherosclerosis via the Ereg/MAPK signalling pathway. PG - 45-58 LID - S0021-9150(23)00192-2 [pii] LID - 10.1016/j.atherosclerosis.2023.05.009 [doi] AB - BACKGROUND AND AIMS: Lactylation, a recently identified post-translational modification (PTM), plays a central role in the regulation of multiple physiological and pathological processes. Exercise is known to provide protection against cardiovascular disease. However, whether exercise-generated lactate changes lactylation and is involved in the exercise-induced attenuation of atherosclerotic cardiovascular disease (ASCVD) remains unclear. The purpose of this study was to investigate the effects and mechanisms of exercise-induced lactylation on ASCVD. METHODS AND RESULTS: Using the high-fat diet-induced apolipoprotein-deficient mouse model of ASCVD, we found that exercise training promoted Mecp2 lysine lactylation (Mecp2k271la); it also decreased the expression of vascular cell adhesion molecule 1 (Vcam-1), intercellular adhesion molecule 1 (Icam-1), monocyte chemoattractant protein 1 (Mcp-1), interleukin (IL)-1beta, IL-6, and increased the level of endothelial nitric oxide synthase (Enos) in the aortic tissue of mice. To explore the underlying mechanisms, mouse aortic endothelial cells (MAECs) were subjected to RNA-sequencing and CHIP-qPCR, which confirmed that Mecp2k271la repressed the expression of epiregulin (Ereg) by binding to its chromatin, demonstrating Ereg as a key downstream molecule for Mecp2k271la. Furthermore, Ereg altered the mitogen-activated protein kinase (MAPK) signalling pathway through regulating the phosphorylation level of epidermal growth factor receptor, thereby affecting the expression of Vcam-1, Icam-1, Mcp-1, IL-1beta, IL-6, and Enos in ECs, which in turn promoted the regression of atherosclerosis. In addition, increasing the level of Mecp2k271la by exogenous lactate administration in vivo also inhibits the expression of Ereg and the MAPK activity in ECs, resulting in repressed atherosclerotic progression. CONCLUSIONS: In summary, this study provides a mechanistic link between exercise and lactylation modification, offering new insight into the anti-atherosclerotic effects of exercise-induced PTM. CI - Copyright (c) 2023 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Wang, Yanan AU - Wang Y AD - Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China. FAU - Chen, Liangqi AU - Chen L AD - Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China. FAU - Zhang, Meiju AU - Zhang M AD - Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China. FAU - Li, Xin AU - Li X AD - Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China. FAU - Yang, Xueyan AU - Yang X AD - Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China. FAU - Huang, Tuo AU - Huang T AD - Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China. FAU - Ban, Yunting AU - Ban Y AD - Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China. FAU - Li, Yunqi AU - Li Y AD - Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China. FAU - Li, Qifeng AU - Li Q AD - Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China. FAU - Zheng, Yang AU - Zheng Y AD - Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China. Electronic address: zhengyanghmu@163.com. FAU - Sun, Yong AU - Sun Y AD - Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China. Electronic address: ssunyyong@126.com. FAU - Wu, Jian AU - Wu J AD - Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Cardiac Rehabilitation Center, Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. Electronic address: wujian780805@163.com. FAU - Yu, Bo AU - Yu B AD - Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China; The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Cardiac Rehabilitation Center, Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230511 PL - Ireland TA - Atherosclerosis JT - Atherosclerosis JID - 0242543 RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - 126547-89-5 (Intercellular Adhesion Molecule-1) RN - 0 (Interleukin-6) RN - 0 (Epiregulin) RN - 0 (Vascular Cell Adhesion Molecule-1) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 0 (Mecp2 protein, mouse) RN - 0 (Methyl-CpG-Binding Protein 2) SB - IM MH - Mice MH - Animals MH - Mitogen-Activated Protein Kinases/metabolism/pharmacology MH - Endothelial Cells/metabolism MH - Intercellular Adhesion Molecule-1/metabolism MH - Interleukin-6/metabolism MH - Epiregulin/metabolism/pharmacology MH - Vascular Cell Adhesion Molecule-1/metabolism MH - *Cardiovascular Diseases/metabolism MH - *Atherosclerosis/genetics/prevention & control/metabolism MH - Intercellular Signaling Peptides and Proteins/metabolism MH - Methyl-CpG-Binding Protein 2/genetics/metabolism/pharmacology OTO - NOTNLM OT - Atherosclerosis OT - Exercise OT - Lactylation OT - Mecp2 OT - Post-translational modification COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/05/29 00:42 MHDA- 2023/06/19 13:08 CRDT- 2023/05/28 18:07 PHST- 2023/02/20 00:00 [received] PHST- 2023/05/11 00:00 [revised] PHST- 2023/05/11 00:00 [accepted] PHST- 2023/06/19 13:08 [medline] PHST- 2023/05/29 00:42 [pubmed] PHST- 2023/05/28 18:07 [entrez] AID - S0021-9150(23)00192-2 [pii] AID - 10.1016/j.atherosclerosis.2023.05.009 [doi] PST - ppublish SO - Atherosclerosis. 2023 Jun;375:45-58. doi: 10.1016/j.atherosclerosis.2023.05.009. Epub 2023 May 11.