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HMGB1 mediates homocysteine-induced endothelial cells pyroptosis via cathepsin V-dependent pathway
Yiping Leng1, Ruifang Chen2, Runtai Chen2
1The 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.
Insights
High homocysteine (HHcy) triggers vascular inflammation and endothelial cell pyroptosis. High-mobility group box-1 (HMGB1) protein and cathepsin V mediate this process, offering new therapeutic targets for HHcy-associated vascular disease.
Area of Science:
- Vascular Biology
- Cell Death Mechanisms
- Molecular Medicine
Background:
- Hyperhomocysteinemia (HHcy) is linked to vascular inflammation, involving endothelial cell injury and pro-inflammatory cytokine release.
- Pyroptosis, a programmed cell death pathway, releases IL-1β and involves gasdermin cleavage, but its role in HHcy-induced vascular issues is unclear.
- Previous work implicated high-mobility group box-1 (HMGB1) and cathepsin V in HHcy-induced endothelial inflammation.
Purpose of the Study:
- To investigate the role of HMGB1 and cathepsin V in homocysteine (Hcy)-induced endothelial cell pyroptosis.
- To elucidate the underlying molecular mechanisms linking Hcy, HMGB1, cathepsin V, and pyroptosis in vascular inflammation.
Main Methods:
- Assessed plasma IL-1β levels in HHcy patients and mouse models.
- Utilized cathepsin V inhibitors in HHcy mice to evaluate effects on IL-1β and GSDMD cleavage.
- Employed cultured human umbilical vein endothelial cells (HUVECs) to study Hcy effects, including gene silencing of GSDMD and HMGB1, and assessed lysosome permeability and caspase-1 activation.
Main Results:
- HHcy patients and mice exhibited elevated plasma IL-1β.
- Cathepsin V inhibition reduced IL-1β and GSDMD cleavage in HHcy mice.
- Hcy promoted GSDMD N-terminal expression in HUVECs; silencing GSDMD or HMGB1 mitigated pyroptosis.
- HMGB1 increased GSDMD N-terminal expression and lysosome permeability; cathepsin V silencing reversed HMGB1-induced pyroptosis and caspase-1 activation.
Conclusions:
- HMGB1 mediates Hcy-induced endothelial cell pyroptosis through a pathway involving cathepsin V.
- This study reveals a novel HMGB1-cathepsin V-dependent mechanism in HHcy-associated vascular inflammation.
- Targeting HMGB1 and cathepsin V may offer therapeutic strategies for hyperhomocysteinemia-related vascular diseases.
Abstract:
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-1β 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-1β levels in HHcy patients and mice models, cathepsin V inhibitor reduced the plasma IL-1β 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.
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