PMID- 32912629 OWN - NLM STAT- MEDLINE DCOM- 20210311 LR - 20210311 IS - 1090-2104 (Electronic) IS - 0006-291X (Linking) VI - 532 IP - 4 DP - 2020 Nov 19 TI - HMGB1 mediates homocysteine-induced endothelial cells pyroptosis via cathepsin V-dependent pathway. PG - 640-646 LID - S0006-291X(20)31691-0 [pii] LID - 10.1016/j.bbrc.2020.08.091 [doi] AB - Endothelial cells injury and pro-inflammation cytokines release are the initial steps of hyperhomocysteinemia (HHcy)-associated vascular inflammation. Pyroptosis is a newly identified pro-inflammation form of programmed cell death, causing cell lysis and IL-1beta release, and characterized by the caspases-induced cleavage of its effector molecule gasdermins (GSDMs). However, the effect of homocysteine (Hcy) on endothelial cells pyroptosis and the underlying mechanisms have not been fully defined. We have previously reported that Hcy induces vascular endothelial inflammation accompanied by the increase of high mobility group box-1 protein (HMGB1) and lysosomal cysteine protease cathepsin V in endothelial cells, and other studies have shown that HMGB1 or cathepsins are involved in activation of NLRP3 inflammasome and caspase-1. Here, we investigated the role of HMGB1 and cathepsin V in the process of Hcy-induced pyroptosis. We observed an increase in plasma IL-1beta levels in HHcy patients and mice models, cathepsin V inhibitor reduced the plasma IL-1beta levels and cleavage of GSDMD full-length into GSDMD N-terminal in the thoracic aorta of hyperhomocysteinemia mice. Using cultured HUVECs, we observed that Hcy promoted GSDMD N-terminal expression, silencing GSDMD or HMGB1 rescued Hcy-induced pyroptosis. HMGB1 also increased GSDMD N-terminal expression, and silencing cathepsin V reversed HMGB1-induced pyroptosis. HMGB1 could increase lysosome permeability, and silencing cathepsin V attenuated HMGB1-induced activation of caspase-1. In conclusion, this study has delineated a novel mechanism that HMGB1 mediated Hcy-induced endothelial cells pyroptosis partly via cathepsin V-dependent pathway. CI - Copyright (c) 2020 Elsevier Inc. All rights reserved. FAU - Leng, Yiping AU - Leng Y AD - The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Postdoctoral Station of Clinical Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China. FAU - Chen, Ruifang AU - Chen R AD - The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China. FAU - Chen, Runtai AU - Chen R AD - The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China. FAU - He, Si AU - He S AD - The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China. FAU - Shi, Xiaoli AU - Shi X AD - The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China. FAU - Zhou, Xiaoyu AU - Zhou X AD - The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China. FAU - Zhang, Zhen AU - Zhang Z AD - The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China. FAU - Chen, Alex F AU - Chen AF AD - The Center for Vascular Disease and Translational Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Cardiology, Institute for Cardiovascular Development and Regenerative Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address: chenfengyuan@xinhuamed.com.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200907 PL - United States TA - Biochem Biophys Res Commun JT - Biochemical and biophysical research communications JID - 0372516 RN - 0 (GSDMD protein, human) RN - 0 (HMGB1 Protein) RN - 0 (Interleukin-1beta) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Phosphate-Binding Proteins) RN - 0LVT1QZ0BA (Homocysteine) RN - EC 3.4.- (Cathepsins) RN - EC 3.4.22.- (Cysteine Endopeptidases) RN - EC 3.4.22.36 (Caspase 1) RN - EC 3.4.22.43 (CTSV protein, human) SB - IM MH - Aged MH - Animals MH - Caspase 1/metabolism MH - Cathepsins/*physiology MH - Cell Line MH - Cysteine Endopeptidases/*physiology MH - Endothelium, Vascular/*cytology MH - Female MH - HMGB1 Protein/*physiology MH - Homocysteine/*physiology MH - Human Umbilical Vein Endothelial Cells/cytology/metabolism MH - Humans MH - Hyperhomocysteinemia/blood/metabolism MH - Interleukin-1beta/blood MH - Intracellular Signaling Peptides and Proteins/metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Middle Aged MH - Phosphate-Binding Proteins/metabolism MH - *Pyroptosis MH - Thoracic Arteries/metabolism OTO - NOTNLM OT - Cathepsin V OT - Endothelial cells OT - High mobility group box-1 protein OT - Homocysteine OT - Pyroptosis COIS- Declaration of competing interest The authors declare that they have no conflicts of interests. EDAT- 2020/09/12 06:00 MHDA- 2021/03/12 06:00 CRDT- 2020/09/11 05:36 PHST- 2020/08/12 00:00 [received] PHST- 2020/08/24 00:00 [accepted] PHST- 2020/09/12 06:00 [pubmed] PHST- 2021/03/12 06:00 [medline] PHST- 2020/09/11 05:36 [entrez] AID - S0006-291X(20)31691-0 [pii] AID - 10.1016/j.bbrc.2020.08.091 [doi] PST - ppublish SO - Biochem Biophys Res Commun. 2020 Nov 19;532(4):640-646. doi: 10.1016/j.bbrc.2020.08.091. Epub 2020 Sep 7.