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 Epub Date: 2024-12-05 DOI:10.1016/j.intimp.2024.113721
Yunfan Li, Xiaojin Zhang, Guohua Jiang, Xinxu Min, Qiuyue Kong, Li Liu, Jun Wu, Zhengnian Ding
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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.

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来源期刊
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.
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