N-myc downstream-regulated gene 4, up-regulated by tumor necrosis factor-alpha and nuclear factor kappa B, aggravates cardiac ischemia/reperfusion injury by inhibiting reperfusion injury salvage kinase pathway
N-myc downstream-regulated gene 4, up-regulated by tumor necrosis factor-alpha and nuclear factor kappa B, aggravates cardiac ischemia/reperfusion injury by inhibiting reperfusion injury salvage kinase pathway
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N-myc下游调控基因4，被肿瘤坏死因子-α和核因子κB上调，通过抑制再灌注损伤挽救激酶途径加重心脏缺血/再灌注损伤
DOI：
10.1007/s00395-015-0519-0
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发表时间：
2016
影响因子：
9.5
通讯作者：
Zhang Yuan-qiang
中科院分区：
文献类型：
--
作者：
Xing Yuan;Tang Bin;Zhu Chao;Li Wei;Li Zhen;Zhao Jie;Gong Wei-dong;Wu Zhi-qun;Zhu Chu-chao;Zhang Yuan-qiang
N-myc下游调节基因4 （NDRG4）在心脏中表达较弱，据报道可调节心脏发育和QT间期持续时间，但NDRG4在心肌缺血/再灌注（I/R）损伤中的作用尚不清楚。在本研究中，我们分析了心脏NDRG4的表达及其潜在功能，并研究了NDRG4的表达如何受到炎症的调节。我们发现NDRG4在心肌细胞中表达较弱，在I/R损伤心脏和缺氧-再氧（H/R）损伤的新生大鼠心室肌细胞（nrvm）中表达显著增加。NDRG4表达增加通过抑制再灌注损伤挽救激酶（RISK）通路的激活而加重心肌I/R损伤。NDRG4的过度表达不仅在I/R损伤的心脏中抑制了RISK的激活并加重了损伤，在H/R处理的nrvm中也是如此，而短发夹RNA （shRNA）介导的NDRG4的敲低增强了RISK的激活并减轻了损伤。损伤后，肿瘤坏死因子-α (TNF-α)通过核因子κB （NF-κB）诱导心肌NDRG4表达，我们发现TNF-α或NF-κB抑制剂预处理可阻断NDRG4表达，抑制体内I/R损伤和体外H/R损伤。我们的研究表明，NDRG4的上调通过抑制RISK通路的激活而加重心肌I/R损伤，从而确定NDRG4是I/R损伤的潜在治疗靶点。
N-myc downstream-regulated gene 4 (NDRG4) is expressed weakly in heart and has been reported to modulate cardiac development and QT interval duration, but the role of NDRG4 in myocardial ischemia/reperfusion (I/R) injury remains unknown. In the present study, we analyzed the expression as well as potential function of cardiac NDRG4 and investigated how NDRG4 expression is regulated by inflammation. We found that NDRG4 was weakly expressed in cardiomyocytes and that its expression increased significantly both in I/R injured heart and in hypoxia-reoxygenation (H/R) injured neonatal rat ventricular myocytes (NRVMs). The increased NDRG4 expression aggravated myocardial I/R injury by inhibiting the activation of the reperfusion injury salvage kinase (RISK) pathway. Forced over-expression of NDRG4 inhibited RISK activation and exacerbated injury not only in I/R injured heart, but also in H/R treated NRVMs, whereas short hairpin RNA (shRNA)-mediated knock-down of NDRG4 enhanced RISK activation and attenuated injury. Upon injury, myocardial NDRG4 expression was induced by tumor necrosis factor-α (TNF-α) through nuclear factor kappa B (NF-κB), and we found that pre-treatment with inhibitors of either TNF-α or NF-κB blocked NDRG4 expression as well as I/R injury in vivo and H/R injury in vitro. Our study indicates that up-regulation of NDRG4 aggravates myocardial I/R injury by inhibiting activation of the RISK pathway, thereby identifying NDRG4 as a potential therapeutic target in I/R injury.