心肌缺血再灌注损伤可通过 HIF-1α 和 c-Jun 通路上调 nucleostemin 的表达,并通过促进自噬缓解细胞凋亡。

IF 6.1 2区 生物学 Q1 CELL BIOLOGY
Xiao Han, Zhicheng Jiang, Yufeng Hou, Xiaorong Zhou, Baoying Hu
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引用次数: 0

摘要

心肌缺血再灌注(I/R)损伤通常产生于急性心肌梗死的介入治疗,会导致心肌细胞不可逆转的死亡。以往的研究表明,心肌缺血再灌注损伤可诱导核固缩蛋白(NS)并减轻心肌细胞凋亡,但对其潜在机制却知之甚少。在此,我们的研究揭示了 NS 的上调对于防止心肌细胞在心肌 I/R 损伤后死亡至关重要。在心肌I/R损伤小鼠和大鼠模型以及缺氧/再氧合(H/R)心脏细胞系(H9C2细胞)中都观察到了NS蛋白水平的升高。我们在 NS 启动子区域发现了 c-Jun 和 HIF-1α 的结合位点。抑制 JNK 和 HIF-1α 可显著降低 NS 的转录和蛋白表达。此外,抑制自噬和NS表达可促进H/R中心肌细胞的凋亡。值得注意的是,H/R 细胞中的 NS 干扰后,细胞模型显示 LC3I 向 LC3II 转化减少,Beclin1 下调,p62 上调,自噬相关蛋白表达改变。这些研究结果表明,NS的表达在c-Jun和HIF-1α通路的驱动下促进了自噬,为防止心肌I/R损伤和H/R诱导的心肌细胞凋亡提供了保护。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Myocardial ischemia-reperfusion injury upregulates nucleostemin expression via HIF-1α and c-Jun pathways and alleviates apoptosis by promoting autophagy.

Myocardial ischemia-reperfusion (I/R) injury, often arising from interventional therapy for acute myocardial infarction, leads to irreversible myocardial cell death. While previous studies indicate that nucleostemin (NS) is induced by myocardial I/R injury and mitigates myocardial cell apoptosis, the underlying mechanisms are poorly understood. Here, our study reveals that NS upregulation is critical for preventing cardiomyocyte death following myocardial I/R injury. Elevated NS protein levels were observed in myocardial I/R injury mouse and rat models, as well as Hypoxia/reoxygenation (H/R) cardiac cell lines (H9C2 cells). We identified binding sites for c-Jun and HIF-1α in the NS promoter region. Inhibition of JNK and HIF-1α led to a significant decrease in NS transcription and protein expression. Furthermore, inhibition of autophagy and NS expression promoted myocardial cell apoptosis in H/R. Notably, the cell model showed reduced LC3I transformation to LC3II, downregulated Beclin1, upregulated p62, and altered expression of autophagy-related proteins upon NS interference in H/R cells. These findings suggest that NS expression, driven by c-Jun and HIF-1α pathways, facilitates autophagy, providing protection against both myocardial I/R injury and H/R-induced cardiomyocyte apoptosis.

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来源期刊
Cell Death Discovery
Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
8.30
自引率
1.40%
发文量
468
审稿时长
9 weeks
期刊介绍: Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.
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