N-myc downstream-regulated gene 4, up-regulated by tumor necrosis factor-α and nuclear factor kappa B, aggravates cardiac ischemia/reperfusion injury by inhibiting reperfusion injury salvage kinase pathway

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• 作者：Yuan Xing ; Bin Tang ; Chao Zhu ; Wei Li ; Zhen Li ; Jie Zhao…
• 关键词：N ; myc downstream ; regulated gene 4 (NDRG4) ; Ischemia/reperfusion (I/R) ; Tumor necrosis factor ; α (TNF ; α) ; Nuclear factor kappa B (NF ; κB) ; Reperfusion injury salvage kinase (RISK)
• 刊名：Basic Research in Cardiology
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：111
• 期：2
• 全文大小：3,085 KB
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• 作者单位：Yuan Xing (1)
  Bin Tang (2)
  Chao Zhu (3)
  Wei Li (4)
  Zhen Li (4)
  Jie Zhao (4)
  Wei-dong Gong (5)
  Zhi-qun Wu (5)
  Chu-chao Zhu (4)
  Yuan-qiang Zhang (4)
  
  1. Department of Physiology, Fourth Military Medical University, Xi’an, 710032, China
  2. Department of International Medical, China-Japan Frindship Hospital, Beijing, 100029, China
  3. Institute of Orthopaedics, Xi’jing Hospital, Fourth Military Medical University, Xi’an, 710032, China
  4. Department of Histology and Embryology, Fourth Military Medical University, Xi’an, 710032, China
  5. Department of Interventional Radiology, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710038, China
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Cardiology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1435-1803

文摘

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. Keywords N-myc downstream-regulated gene 4 (NDRG4) Ischemia/reperfusion (I/R) Tumor necrosis factor-α (TNF-α) Nuclear factor kappa B (NF-κB) Reperfusion injury salvage kinase (RISK)