Downregulation of HSPA12A protects heart against sepsis through suppressing mTOR-mediated inflammatory response in cardiomyocytes

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-01-03 DOI:10.1016/j.intimp.2024.113721

Yunfan Li , Xiaojin Zhang , Guohua Jiang , Xinxu Min , Qiuyue Kong , Li Liu , Jun Wu , Zhengnian Ding

{"title":"Downregulation of HSPA12A protects heart against sepsis through suppressing mTOR-mediated inflammatory response in cardiomyocytes","authors":"Yunfan Li , Xiaojin Zhang , Guohua Jiang , Xinxu Min , Qiuyue Kong , Li Liu , Jun Wu , Zhengnian Ding","doi":"10.1016/j.intimp.2024.113721","DOIUrl":null,"url":null,"abstract":"<div><h3>Objective</h3><div>Over-activated immune response in hearts is the main pathological feature of septic cardiomyopathy, a fatal complication of sepsis with high mortality. Autophagy is capable to limit immune response by removing inflammatory mediators. Heat shock protein A12A (HSPA12A) encodes an atypical member of HSP70 family. This study aimed to investigate the role of HSPA12A in septic cardiomyopathy.</div></div><div><h3>Methods</h3><div>Sepsis was induced by cecal ligation and puncture (CLP) for 6 h in mice <em>in vivo</em> or by LPS treatment for 24 h in primary cardiomyocytes <em>in vitro</em>. HSPA12A knockout (<em>Hspa12a<sup>−/−</sup></em>) mice were generated by cre-loxp system. Echocardiography was performed to assess cardiac function. TUNEL and propidium iodide (PI) staining was used to indicate cardiomyocyte death. Inflammation-related factors were examined by qPCR and immunoblotting. Autophagy was evaluated by levels of LC3-II and p62.</div></div><div><h3>Results</h3><div>Sepsis decreased HSPA12A expression in hearts and cardiomyocytes, while HSPA12A knockout in mice attenuated sepsis-induced cardiomyocyte death and cardiac dysfunction. Sepsis-induced activation of TLR4/MyD88/NF-κB-mediated inflammation was inhibited in hearts by HSPA12A knockout whereas was enhanced by HSPA12A overexpression in cardiomyocytes. Moreover, HSPA12A overexpression activated mTOR and inhibited autophagy in cardiomyocytes, while inhibition of mTOR by rapamycin diminished the HSPA12A-induced autophagy inhibition, inflammation activation, and cardiomyocyte death in septic cardiomyocytes.</div></div><div><h3>Conclusion</h3><div>Downregulation of HSPA12A inhibited mTOR to activated autophagy, thereby suppressed inflammatory response, and ultimately attenuated septic cardiomyopathy. Our findings identified HSPA12A as a driver for septic cardiomyopathy development, and strategies that inhibit HSPA12A in cardiomyocytes might be a potential therapeutic intervention.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"145 ","pages":"Article 113721"},"PeriodicalIF":4.8000,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International immunopharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1567576924022434","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Objective

Over-activated immune response in hearts is the main pathological feature of septic cardiomyopathy, a fatal complication of sepsis with high mortality. Autophagy is capable to limit immune response by removing inflammatory mediators. Heat shock protein A12A (HSPA12A) encodes an atypical member of HSP70 family. This study aimed to investigate the role of HSPA12A in septic cardiomyopathy.

Methods

Sepsis was induced by cecal ligation and puncture (CLP) for 6 h in mice in vivo or by LPS treatment for 24 h in primary cardiomyocytes in vitro. HSPA12A knockout (Hspa12a^−/−) mice were generated by cre-loxp system. Echocardiography was performed to assess cardiac function. TUNEL and propidium iodide (PI) staining was used to indicate cardiomyocyte death. Inflammation-related factors were examined by qPCR and immunoblotting. Autophagy was evaluated by levels of LC3-II and p62.

Results

Sepsis decreased HSPA12A expression in hearts and cardiomyocytes, while HSPA12A knockout in mice attenuated sepsis-induced cardiomyocyte death and cardiac dysfunction. Sepsis-induced activation of TLR4/MyD88/NF-κB-mediated inflammation was inhibited in hearts by HSPA12A knockout whereas was enhanced by HSPA12A overexpression in cardiomyocytes. Moreover, HSPA12A overexpression activated mTOR and inhibited autophagy in cardiomyocytes, while inhibition of mTOR by rapamycin diminished the HSPA12A-induced autophagy inhibition, inflammation activation, and cardiomyocyte death in septic cardiomyocytes.

Conclusion

Downregulation of HSPA12A inhibited mTOR to activated autophagy, thereby suppressed inflammatory response, and ultimately attenuated septic cardiomyopathy. Our findings identified HSPA12A as a driver for septic cardiomyopathy development, and strategies that inhibit HSPA12A in cardiomyocytes might be a potential therapeutic intervention.

Abstract Image

查看原文本刊更多论文

HSPA12A的下调通过抑制mtor介导的心肌细胞炎症反应来保护心脏免受败血症的侵袭。

目的：心脏过度激活的免疫反应是脓毒症心肌病的主要病理特征，是脓毒症的致命并发症，死亡率高。自噬能够通过清除炎症介质来限制免疫反应。热休克蛋白A12A （HSPA12A）编码HSP70家族的一个非典型成员。本研究旨在探讨HSPA12A在脓毒性心肌病中的作用。方法：小鼠体内用盲肠结扎穿刺法（CLP）致脓毒症6 h，体外用原代心肌细胞LPS处理24 h。cre-loxp法制备HSPA12A敲除小鼠（HSPA12A -/-）。超声心动图评估心功能。TUNEL和碘化丙啶（PI）染色显示心肌细胞死亡。采用qPCR和免疫印迹法检测炎症相关因素。通过LC3-II和p62水平评估自噬。结果：脓毒症降低心脏和心肌细胞中HSPA12A的表达，而敲除小鼠HSPA12A可减轻脓毒症诱导的心肌细胞死亡和心功能障碍。HSPA12A敲除可抑制败血症诱导的TLR4/MyD88/NF-κ b介导的炎症在心脏中的激活，而HSPA12A在心肌细胞中的过表达可增强这种激活。此外，HSPA12A过表达激活mTOR并抑制心肌细胞自噬，而雷帕霉素抑制mTOR可减轻HSPA12A诱导的脓毒症心肌细胞自噬抑制、炎症激活和心肌细胞死亡。结论：下调HSPA12A可抑制mTOR激活自噬，从而抑制炎症反应，最终减轻脓毒性心肌病。我们的研究结果确定HSPA12A是脓毒性心肌病发展的驱动因素，抑制心肌细胞HSPA12A的策略可能是一种潜在的治疗干预。

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

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.