PLD2 deletion ameliorates sepsis-induced cardiomyopathy by suppressing cardiomyocyte pyroptosis via the NLRP3/caspase 1/GSDMD pathway

IF 4.8 3区 医学 Q2 CELL BIOLOGY
Jun Li, Da Teng, Wenjuan Jia, Lei Gong, Haibin Dong, Chunxiao Wang, Lihui Zhang, Bowen Xu, Wenlong Wang, Lin Zhong, Jianxun Wang, Jun Yang
{"title":"PLD2 deletion ameliorates sepsis-induced cardiomyopathy by suppressing cardiomyocyte pyroptosis via the NLRP3/caspase 1/GSDMD pathway","authors":"Jun Li, Da Teng, Wenjuan Jia, Lei Gong, Haibin Dong, Chunxiao Wang, Lihui Zhang, Bowen Xu, Wenlong Wang, Lin Zhong, Jianxun Wang, Jun Yang","doi":"10.1007/s00011-024-01881-w","DOIUrl":null,"url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Objective</h3><p>Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication. Phospholipase D2 (PLD2) is crucial in mediating inflammatory reactions and is associated with the prognosis of patients with sepsis. Whether PLD2 is involved in the pathophysiology of SICM remains unknown. This study aimed to investigate the effect of PLD2 knockout on SICM and to explore potential mechanisms.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>The SICM model was established using cecal ligation and puncture in wild-type and PLD2-knockout mice and lipopolysaccharide (LPS)-induced H9C2 cardiomyocytes. Transfection with PLD2-shRNA lentivirus and a PLD2 overexpression plasmid were used to interfere with PLD2 expression in H9C2 cells. Cardiac pathological alterations, cardiac function, markers of myocardial injury, and inflammatory factors were used to evaluate the SICM model. The expression of pyroptosis-related proteins (NLRP3, cleaved caspase 1, and GSDMD-N) was assessed using western blotting, immunofluorescence, and immunohistochemistry.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>SICM mice had myocardial tissue damage, increased inflammatory response, and impaired heart function, accompanied by elevated PLD2 expression. PLD2 deletion improved cardiac histological changes, mitigated cTNI production, and enhanced the survival of the SICM mice. Compared with controls, PLD2-knockdown H9C2 exhibits a decrease in inflammatory markers and lactate dehydrogenase production, and scanning electron microscopy results suggest that pyroptosis may be involved. The overexpression of PLD2 increased the expression of NLRP3 in cardiomyocytes. In addition, PLD2 deletion decreased the expression of pyroptosis-related proteins in SICM mice and LPS-induced H9C2 cells.</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>PLD2 deletion is involved in SICM pathogenesis and is associated with the inhibition of the myocardial inflammatory response and pyroptosis through the NLRP3/caspase 1/GSDMD pathway.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"27 1","pages":""},"PeriodicalIF":4.8000,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Inflammation Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00011-024-01881-w","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Objective

Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication. Phospholipase D2 (PLD2) is crucial in mediating inflammatory reactions and is associated with the prognosis of patients with sepsis. Whether PLD2 is involved in the pathophysiology of SICM remains unknown. This study aimed to investigate the effect of PLD2 knockout on SICM and to explore potential mechanisms.

Methods

The SICM model was established using cecal ligation and puncture in wild-type and PLD2-knockout mice and lipopolysaccharide (LPS)-induced H9C2 cardiomyocytes. Transfection with PLD2-shRNA lentivirus and a PLD2 overexpression plasmid were used to interfere with PLD2 expression in H9C2 cells. Cardiac pathological alterations, cardiac function, markers of myocardial injury, and inflammatory factors were used to evaluate the SICM model. The expression of pyroptosis-related proteins (NLRP3, cleaved caspase 1, and GSDMD-N) was assessed using western blotting, immunofluorescence, and immunohistochemistry.

Results

SICM mice had myocardial tissue damage, increased inflammatory response, and impaired heart function, accompanied by elevated PLD2 expression. PLD2 deletion improved cardiac histological changes, mitigated cTNI production, and enhanced the survival of the SICM mice. Compared with controls, PLD2-knockdown H9C2 exhibits a decrease in inflammatory markers and lactate dehydrogenase production, and scanning electron microscopy results suggest that pyroptosis may be involved. The overexpression of PLD2 increased the expression of NLRP3 in cardiomyocytes. In addition, PLD2 deletion decreased the expression of pyroptosis-related proteins in SICM mice and LPS-induced H9C2 cells.

Conclusion

PLD2 deletion is involved in SICM pathogenesis and is associated with the inhibition of the myocardial inflammatory response and pyroptosis through the NLRP3/caspase 1/GSDMD pathway.

Abstract Image

删除 PLD2 可通过 NLRP3/caspase 1/GSDMD 途径抑制心肌细胞的脓毒症,从而改善败血症诱发的心肌病
目的败血症诱发的心肌病(SICM)是一种危及生命的并发症。磷脂酶 D2(PLD2)是介导炎症反应的关键,与败血症患者的预后有关。PLD2 是否参与了 SICM 的病理生理学仍是未知数。本研究旨在研究 PLD2 基因敲除对 SICM 的影响,并探讨其潜在机制。方法利用野生型和 PLD2 基因敲除小鼠的盲肠结扎和穿刺以及脂多糖(LPS)诱导的 H9C2 心肌细胞建立 SICM 模型。用PLD2-shRNA慢病毒和PLD2过表达质粒转染干扰PLD2在H9C2细胞中的表达。心脏病理改变、心脏功能、心肌损伤标志物和炎症因子被用来评估SICM模型。结果SICM小鼠有心肌组织损伤、炎症反应增加和心脏功能受损,同时伴有PLD2表达升高。删除 PLD2 可改善心脏组织学变化,减轻 cTNI 的产生,并提高 SICM 小鼠的存活率。与对照组相比,PLD2-敲除的H9C2显示炎症标志物和乳酸脱氢酶生成减少,扫描电子显微镜结果表明这可能与热普特氏症有关。过表达 PLD2 会增加心肌细胞中 NLRP3 的表达。结论PLD2缺失参与了SICM的发病机制,并与通过NLRP3/caspase 1/GSDMD途径抑制心肌炎症反应和热昏迷有关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Inflammation Research
Inflammation Research 医学-免疫学
CiteScore
9.90
自引率
1.50%
发文量
134
审稿时长
3-8 weeks
期刊介绍: Inflammation Research (IR) publishes peer-reviewed papers on all aspects of inflammation and related fields including histopathology, immunological mechanisms, gene expression, mediators, experimental models, clinical investigations and the effect of drugs. Related fields are broadly defined and include for instance, allergy and asthma, shock, pain, joint damage, skin disease as well as clinical trials of relevant drugs.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信