PDCD4通过akt介导的细胞凋亡加重心肌缺血再灌注损伤

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling Pub Date : 2025-07-23 DOI:10.1016/j.cellsig.2025.111999

Zhiming Zhang , Zhihui Yang , Hangbin Ge , Chenyang Liu , Renchenghan Fan , Chenying Yuan , Shengban You , Chenglv Hong

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引用次数: 0

摘要

心肌缺血再灌注（I/R）损伤是心肌梗死再灌注治疗后的重要并发症。细胞凋亡作为I/R损伤的标志，在心肌缺血再灌注损伤中起重要作用。程序性细胞死亡4 （PDCD4）调节MI/RI中的凋亡，但其机制尚未完全阐明。在本研究中，我们证明了心肌I/R损伤模型中PDCD4表达显著上调。体内PDCD4基因缺失可显著降低梗死面积、血清损伤生物标志物（CK-MB、cTnT、LDH）和细胞凋亡。机制上，PDCD4直接与AKT相互作用，通过减少泛素化抑制其磷酸化。抑制AKT活性降低BCL-2水平，促进线粒体凋亡。沉默PDCD4可恢复AKT磷酸化，减轻细胞凋亡，减轻心肌损伤。我们的研究结果表明，PDCD4通过akt介导的细胞凋亡是心肌I/R损伤的关键驱动因素，并强调了其治疗潜力。

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PDCD4 exacerbates myocardial ischemia-reperfusion injury via AKT-mediated apoptosis

Myocardial ischemia-reperfusion (I/R) injury is a critical complication following reperfusion therapy for myocardial infarction. As a marker of I/R injury, apoptosis plays an important role in myocardial ischemia-reperfusion injury. Programmed Cell Death 4 (PDCD4) regulates apoptosis in MI/RI, but the mechanism is not yet fully elucidated. In this study, we demonstrate that PDCD4 expression was significantly upregulated in a myocardial I/R injury model. Genetic deletion of PDCD4 markedly reduced infarct size, serum biomarkers of injury (CK-MB, cTnT, LDH), and apoptosis in vivo. Mechanistically, PDCD4 directly interacts with AKT, inhibiting its phosphorylation by reducing ubiquitination. This suppression of AKT activity decreased BCL-2 levels, promoting mitochondrial apoptosis. Silencing PDCD4 restored AKT phosphorylation, attenuated apoptosis, and alleviated myocardial damage. Our findings establish PDCD4 as a key driver of myocardial I/R injury via AKT-mediated apoptosis and highlight its therapeutic potential.

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来源期刊

Cellular signalling 生物-细胞生物学

CiteScore

8.40

自引率

0.00%

发文量

250

审稿时长

27 days

期刊介绍： Cellular Signalling publishes original research describing fundamental and clinical findings on the mechanisms, actions and structural components of cellular signalling systems in vitro and in vivo. Cellular Signalling aims at full length research papers defining signalling systems ranging from microorganisms to cells, tissues and higher organisms.