Interferon regulatory factor 9 is an essential mediator of heart dysfunction and cell death following myocardial ischemia/reperfusion injury
Interferon regulatory factor 9 is an essential mediator of heart dysfunction and cell death following myocardial ischemia/reperfusion injury
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干扰素调节因子 9 是心肌缺血/再灌注损伤后心功能障碍和细胞死亡的重要介质。
DOI：
10.1007/s00395-014-0434-9
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发表时间：
2014-09-01
影响因子：
9.5
通讯作者：
Li, Hongliang
中科院分区：
文献类型：
--
作者：
Zhang, Yan;Liu, Xiaoxiong;Li, Hongliang
本研究旨在探讨干扰素调节因子9(IRF9)是否参与心肌缺血再灌注(I/R)损伤的发病机制及其分子机制。细胞死亡在心肌I/R损伤中起主要作用。我们最近确定了IRF9在协调心肌细胞肥大应激反应的分子事件中的重要性。然而，IRF9在致死性心肌损伤中的作用尚不清楚。在小鼠心肌I/R损伤模型中，通过基因敲除和心肌细胞特异性转基因过表达来评价IRF9的参与，并在体内和体外进一步研究其对心肌细胞凋亡和炎症的影响。IRF9在人缺血心肌组织和小鼠心肌I/R损伤后表达上调。消融IRF9可保护心脏免受I/R引起的心肌细胞死亡、炎症发展和心功能丧失的影响。相反，心肌细胞特异性的IRF9转基因过表达加剧了心肌再灌注损伤和炎症。在体内外I/R条件下，IRF9对Sirt1-P53轴具有负性调节作用。由I/R引起的Sirt1表达下调及其下游的凋亡相关信号级联反应可因IRF9的缺失而改善，并因IRF9的过表达而加剧。心肌细胞特异性Sirt1基因的缺失取消了IRF9基因敲除对心肌I/R损伤的保护作用，进一步表明IRF9通过调节Sirt1-P53轴介导心肌再灌注损伤。因此，IRF9可能成为预防急性心肌梗死后血管重建所致I/R损伤的一个新的治疗靶点。
This study aimed to investigate whether interferon regulatory factor 9 (IRF9) is involved in the pathogenesis of myocardial ischemia-reperfusion (I/R) injury and to explore the underlying molecular mechanisms of this process. Cell death plays a major role in myocardial I/R injury. We recently determined the importance of IRF9 in coordinating molecular events in response to hypertrophic stress in cardiomyocytes. However, the roles of IRF9 in lethal myocardial injury remain to be elucidated. The involvement of IRF9 was assessed via functional assays in a mouse myocardial I/R injury model by genetic knockout and cardiomyocyte-specific transgenic overexpression of IRF9, and its effects on cardiomyocyte apoptosis and inflammation were further studied in vivo and in vitro. IRF9 was upregulated in human ischemic heart tissue and mouse hearts after I/R injury. Ablation of IRF9 protected the heart against I/R-induced cardiomyocyte death, development of inflammation, and loss of heart function. In contrast, cardiomyocyte-specific transgenic overexpression of IRF9 aggravated myocardial reperfusion injury and inflammation. IRF9 negatively regulated the Sirt1-p53 axis under I/R conditions in vivo and in vitro. Downregulation of Sirt1 expression and its downstream apoptosis-related signaling cascade, which results from I/R, was ameliorated by loss of IRF9 and exacerbated by overexpression of IRF9. Cardiomyocyte-specific deletion of Sirt1 abolished the protective effect of IRF9 knockout against I/R injury, which further indicated that IRF9 mediated myocardial reperfusion injury by modulating the Sirt1-p53 axis. Thus, IRF9 may be a novel therapeutic target for the prevention of I/R injury resulting from revascularization therapy after acute myocardial infarction (MI).