PMID- 37976692 OWN - NLM STAT- MEDLINE DCOM- 20240117 LR - 20240117 IS - 1618-095X (Electronic) IS - 0944-7113 (Linking) VI - 123 DP - 2024 Jan TI - Lupeol alleviates autoimmune myocarditis by suppressing macrophage pyroptosis and polarization via PPARalpha/LACC1/NF-kappaB signaling pathway. PG - 155193 LID - S0944-7113(23)00552-4 [pii] LID - 10.1016/j.phymed.2023.155193 [doi] AB - BACKGROUND: Autoimmune myocarditis, with increasing incidence and limited therapeutic strategies, is in urgent need to explore its underlying mechanisms and effective drugs. Pyroptosis is a programmed cell death that may contribute to the pathogenesis of myocarditis. Nonetheless, no direct evidence validated the role of pyroptosis in autoimmune myocarditis. Lupeol (Lup), a pentacyclic triterpene, possesses various biological activities such as antidiabetic properties. However, the effects of Lup on autoimmune myocarditis and pyroptosis remain unelucidated. PURPOSE: This study aimed to reveal the role of pyroptosis in autoimmune myocarditis and explore the protective effects of Lup, and its engaged mechanisms. METHODS: The experimental autoimmune myocarditis (EAM) mouse model was established by immunization with a fragment of cardiac myosin in Balb/c mice. Lup and MCC950 were administered after EAM induction. The protective effects were assessed by inflammation score, cardiac injury, chronic fibrosis, and cardiac function. Mechanistically, the effects of Lup on the M1 polarization and pyroptosis of macrophages were evaluated. Transcriptome sequencing and molecular docking were subsequently employed, and the underlying mechanisms of Lup were further explored in vitro with small interfering RNA and adenovirus. RESULTS: Administration of Lup and MCC950 alleviated EAM progression. Western blotting and immunofluorescence staining identified macrophages as the primary cells undergoing pyroptosis. Lup inhibited the expression of pyroptosis-associated proteins in macrophages during EAM in a dose-dependent manner. Furthermore, Lup suppressed pyroptosis in both bone marrow-derived macrophages (BMDMs) and THP-1-derived macrophages in vitro. In addition, Lup inhibited the M1 polarization of macrophages both in vivo and in vitro. Mechanistically, the protective effects of Lup were demonstrated via the suppression of the nuclear factor-kappaBeta (NF-kappaB) signaling pathway. Transcriptome sequencing and molecular docking revealed the potential involvement of peroxisome proliferator-associated receptor alpha (PPARalpha). Subsequently, we demonstrated that Lup activated PPARalpha to reduce the expression level of LACC1, thereby inhibiting the NF-kappaB pathway and pyroptosis. CONCLUSION: Our findings indicated the crucial role of macrophage pyroptosis in the pathogenesis of EAM. Lup ameliorated EAM by inhibiting the M1 polarization and pyroptosis of macrophages through the PPARalpha/LACC1/NF-kappaB signaling pathway. Thus, our results provided a novel therapeutic target and agent for myocarditis. CI - Copyright (c) 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved. FAU - Xiong, Yulong AU - Xiong Y AD - Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China. FAU - Zhang, Zhenhao AU - Zhang Z AD - Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China. FAU - Liu, Shangyu AU - Liu S AD - Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China. FAU - Shen, Lishui AU - Shen L AD - Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China. FAU - Zheng, Lihui AU - Zheng L AD - Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China. FAU - Ding, Ligang AU - Ding L AD - Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China. FAU - Liu, Limin AU - Liu L AD - Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China. FAU - Wu, Lingmin AU - Wu L AD - Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China. FAU - Li, Le AU - Li L AD - Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China. FAU - Hu, Zhao AU - Hu Z AD - Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China. FAU - Zhang, Zhuxin AU - Zhang Z AD - Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China. FAU - Zhou, Likun AU - Zhou L AD - Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China. FAU - Yao, Yan AU - Yao Y AD - Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China; State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167A Beilishi Road, Xi Cheng District, Beijing 100037, PR China. Electronic address: ianyao@263.net.cn. LA - eng PT - Journal Article DEP - 20231108 PL - Germany TA - Phytomedicine JT - Phytomedicine : international journal of phytotherapy and phytopharmacology JID - 9438794 RN - 0 (NF-kappa B) RN - 0 (PPAR alpha) RN - O268W13H3O (lupeol) RN - 0 (Peroxisome Proliferators) RN - 0 (Pentacyclic Triterpenes) RN - 0 (Lupanes) SB - IM MH - Mice MH - Animals MH - *Myocarditis MH - NF-kappa B/metabolism MH - PPAR alpha MH - *Autoimmune Diseases/drug therapy MH - Pyroptosis MH - Molecular Docking Simulation MH - Peroxisome Proliferators/therapeutic use MH - Signal Transduction MH - Macrophages MH - Pentacyclic Triterpenes/pharmacology MH - *Lupanes OTO - NOTNLM OT - Inflammasome OT - Lupeol OT - Macrophage OT - Myocarditis OT - Pyroptosis COIS- Declaration of Competing Interest All authors declared that no relevant conflicts of interest exist in this study. EDAT- 2023/11/18 11:41 MHDA- 2024/01/17 06:42 CRDT- 2023/11/17 18:07 PHST- 2023/07/18 00:00 [received] PHST- 2023/10/15 00:00 [revised] PHST- 2023/11/06 00:00 [accepted] PHST- 2024/01/17 06:42 [medline] PHST- 2023/11/18 11:41 [pubmed] PHST- 2023/11/17 18:07 [entrez] AID - S0944-7113(23)00552-4 [pii] AID - 10.1016/j.phymed.2023.155193 [doi] PST - ppublish SO - Phytomedicine. 2024 Jan;123:155193. doi: 10.1016/j.phymed.2023.155193. Epub 2023 Nov 8.