分化剪接因子SRSF1信号通路促进cme后炎症:SRSF1/ENPP3轴通过抑制BRD4 o - glcn酰化作用,增强NF-κB活化,加速心力衰竭。

IF 12.4 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-06-09 eCollection Date: 2025-01-01 DOI:10.7150/thno.115402
Chen-Kai Hu, Lei He, Wan-Zhong Huang, Yuan Huang, Ri-Xin Dai, Chen Chang, Jun-Xiong Qiu, Qiang Wu, Qiang Su
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引用次数: 0

摘要

理由:冠状动脉微栓塞(CME)是急性冠状动脉综合征期间发生的一种严重的医学状况,可导致心肌炎症、细胞凋亡和心功能障碍。本研究探讨SRSF1在CME引起的心肌炎症中的生物学功能及其潜在机制。方法:采用左心室注射微球和氧糖剥夺(OGD)暴露心肌细胞建立CME模型。采用RT-qPCR、Western blotting和免疫组化染色检测靶分子的表达情况。流式细胞术检测心肌细胞凋亡。通过RIP和TRAP验证了SRSF1与外核苷酸焦磷酸酶/磷酸二酯酶3 (ENPP3)的直接结合。通过Co-IP测定蛋白相互作用。双荧光素酶报告试验测量炎症细胞因子转录水平。采用HE染色和超声检查评估心肌损伤。该研究使用ELISA检测炎症细胞因子和心肌肌钙蛋白I (cTnI)水平。结果:SRSF1在CME模型中的表达明显增强。SRSF1的下调通过调节ENPP3 pre-mRNA的选择性剪接增加ENPP3 mRNA/lncRNA ENPP3比值,有效抑制NF-κ b介导的心肌炎症。CME过程中含溴结构域蛋白4 (BRD4)的glcn酰化降低,BRD4蛋白水平升高,引发NF-κ b介导的炎症。SRSF1/ENPP3轴抑制CME中BRD4的glcn酰化。心肌特异性敲除SRSF1可通过ENPP3/BRD4/NF-κB通路失活恢复CME大鼠心功能,抑制心肌炎症。结论:SRSF1通过上调ENPP3/lncRNA ENPP3比值抑制BRD4的glcn酰化,促进CME诱导的心肌炎症,提示抑制SRSF1是一种很有前景的CME治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Divergent splicing factor SRSF1 signaling promotes inflammation post-CME: the SRSF1/ENPP3 axis acts via inhibition of BRD4 O-GlcNAcylation to enhance NF-κB activation and accelerate heart failure.

Rationale: Coronary microembolization (CME) is a severe medical condition that occurs during acute coronary syndrome, leading to myocardial inflammation, apoptosis, and cardiac dysfunction. The research investigated SRSF1 biological functions during myocardial inflammation caused by CME and its underlying mechanisms. Methods: CME models were established in rats injected with microspheres in the left ventricle and oxygen-glucose deprivation (OGD)-exposed cardiomyocytes. RT-qPCR, Western blotting and immunohistochemical staining were used to evaluate the expression of target molecules. Myocardial apoptosis was detected by flow cytometry. The direct binding between SRSF1 and ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) was verified by RIP and TRAP. Protein interaction was determined by Co-IP. The dual-luciferase reporter assay measured inflammatory cytokine transcription levels. Myocardial injury was assessed by HE staining and ultrasound examinations. The study used ELISA to measure inflammatory cytokines and cardiac troponin I (cTnI) levels. Results: SRSF1 expression was strikingly enhanced in CME models. Knockdown of SRSF1 effectively restrained NF-κB-mediated myocardial inflammation through increasing ENPP3 mRNA/lncRNA ENPP3 ratio by regulating alternative splicing of ENPP3 pre-mRNA. The GlcNAcylation of bromodomain-containing protein 4 (BRD4) was reduced during CME, which increased BRD4 protein level to trigger NF-κB-mediated inflammation. SRSF1/ENPP3 axis inhibited the GlcNAcylation of BRD4 in CME. Myocardial-specific knockout of SRSF1 restored cardiac function and restrained myocardial inflammation in CME rats by inactivation of the ENPP3/BRD4/NF-κB pathway. Conclusions: SRSF1 facilitates CME-induced myocardial inflammation by up-regulating ENPP3/lncRNA ENPP3 ratio to suppress GlcNAcylation of BRD4, suggesting SRSF1 inhibition as a promising therapeutic strategy for CME.

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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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