USP38通过P53/SLC7A11通路促进铁下垂，加重心肌缺血/再灌注后心肌损伤和恶性室性心律失常。

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-01-03 DOI:10.1016/j.intimp.2024.113727

Yang Gong , Hongjie Yang , Tao Chen , Jingjing Zhang , Bin Kong , Wei Shuai , He Huang

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引用次数: 0

摘要

心肌缺血再灌注（I/R）可导致心肌损伤和恶性室性心律失常（VAs）。铁下垂是一种新的细胞死亡形式，在I/R后心肌损伤中起作用。泛素特异性蛋白酶38 （USP38）是去泛素化酶家族的一员，参与调节炎症和肿瘤的进展，但其在心肌I/R和铁凋亡中的作用尚不清楚。目的：本文探讨USP38是否调节心肌I/ r诱导的铁下垂和恶性心律失常的发生及其机制。方法：本研究通过结扎/松动左前降支建立心脏I/R小鼠模型，采用USP38心脏条件敲除（USP38- cko）小鼠和USP38心脏特异性过表达（USP38- tg）小鼠，研究USP38对I/R诱导的铁下垂和输精管敏感性的影响。此外，通过缺氧/再氧化（H/R）建立体外I/R模型，进一步验证其有效性。结果：我们的研究显示，I/R后USP38的表达明显增加。USP38-CKO显著抑制I/ r诱导的铁超载、ROS产生和脂质过氧化。此外，USP38-CKO改善i /R后电生理异常，降低对VAs的易感性。USP38-TG表现出相反的作用，I/R后加重铁下垂，增加对VAs的敏感性。体内实验同样表明，USP38显著加重了H/ r诱导的铁下垂。在机制上，USP38直接与P53相互作用，调控P53的泛素化水平和下游SLC7A11的表达。结论：我们发现铁下垂与I/R术后VAs显著相关。USP38可通过影响铁下垂调节心肌损伤和VAs易感性，可能与P53/SLC7A11通路有关。

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USP38 exacerbates myocardial injury and malignant ventricular arrhythmias after ischemia/reperfusion by promoting ferroptosis through the P53/SLC7A11 pathway

Introduction

Myocardial ischemia–reperfusion (I/R) leads to myocardial injury and malignant ventricular arrhythmias (VAs). Ferroptosis is a novel form of cell death that plays a role in myocardial injury after I/R. Ubiquitin-specific protease 38 (USP38), a member of the deubiquitinating enzyme family, is involved in regulating the progression of inflammation and tumors, but its role in myocardial I/R and ferroptosis is unclear.

Objectives

Herein, we explored whether USP38 regulates myocardial I/R-induced ferroptosis and the development of malignant arrhythmias and underlying mechanisms.

Methods

In this study, cardiac I/R mice model was established by ligating/loosening the left anterior descending artery, and the effects of USP38 on I/R-induced ferroptosis and VAs susceptibility were investigated using USP38 cardiac conditional knockout (USP38-CKO) mice and USP38 cardiac specific overexpression (USP38-TG) mice. In addition, an in vitro I/R model was constructed by hypoxia/reoxygenation (H/R) for further validation.

Results

Our study showed that USP38 expression was significantly increased after I/R. USP38-CKO significantly inhibited I/R-induced iron overload, ROS production, and lipid peroxidation. In addition, USP38-CKO ameliorates post-I/R electrophysiologic abnormalities and reduces susceptibility to VAs. USP38-TG showed the opposite effect, exacerbating ferroptosis and increasing susceptibility to VAs after I/R. In vivo experiments similarly demonstrated that USP38 significantly exacerbated H/R-induced ferroptosis. Mechanistically, USP38 directly interacts with P53 and regulates the ubiquitination level of P53 and downstream SLC7A11 expression.

Conclusion

We found that ferroptosis was significantly associated with VAs after I/R. USP38 can modulate myocardial injury and VAs susceptibility by affecting ferroptosis, which may be related to the P53/SLC7A11 pathway.

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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.