Department of Physiology, School of Medicine, Ajou University, Suwon 443-749, Republic of Korea.
Cardiovasc Res. 2010 Jul 1;87(1):119-26. doi: 10.1093/cvr/cvq048. Epub 2010 Feb 12.
Because apoptotic death plays a critical role in cardiomyocyte loss during ischaemic heart injury, a detailed understanding of the mechanisms involved is likely to have a substantial impact on the optimization and development of treatment strategies. The goal of this study was to assess gene profiling during ischaemia/hypoxia and to evaluate the functions of ischaemia/hypoxia-responsive genes in in vivo and in vitro ischaemia/hypoxia-induced cardiomyocyte apoptosis models.
DNA microarray analysis and real-time polymerase chain reaction were performed on hearts obtained from an in vivo rat transient ischaemia model and on neonatal rat cardiomyocytes from an in vitro hypoxia model. Three genes, namely Ddit4, Gadd45beta and Atf3, were found to be up-regulated in vivo and in vitro. Using loss-of-function and gain-of-function techniques, the functions of these ischaemia/hypoxia-responsive genes were evaluated. Ischaemia/hypoxia-induced cardiomyocyte apoptosis was remarkably attenuated by the small interfering RNA-mediated down-regulation of Gadd45beta in vivo and in vitro, whereas ectopic Gadd45beta expression significantly aggravated hypoxia-induced apoptosis in vitro.
These results suggest that Gadd45beta is a key player in ischaemia/hypoxia-induced apoptotic cardiomyocyte death, and that strategies based on its inhibition might be of benefit in the treatment of acute ischaemic heart disease.
由于细胞凋亡在缺血性心脏损伤过程中心肌细胞丢失中起着关键作用，因此深入了解相关机制可能会对治疗策略的优化和发展产生重大影响。本研究旨在评估缺血/缺氧过程中的基因谱，并评估缺血/缺氧反应基因在体内和体外缺血/缺氧诱导的心肌细胞凋亡模型中的功能。
对体内大鼠短暂性缺血模型和体外缺氧模型的新生大鼠心肌细胞进行 DNA 微阵列分析和实时聚合酶链反应。发现三种基因，即 Ddit4、Gadd45beta 和 Atf3，在体内和体外均呈上调表达。利用基因敲除和基因过表达技术，评估了这些缺血/缺氧反应基因的功能。体内和体外通过小干扰 RNA 介导的 Gadd45beta 下调显著减轻了缺血/缺氧诱导的心肌细胞凋亡，而异位 Gadd45beta 表达则显著加重了体外缺氧诱导的凋亡。
这些结果表明，Gadd45beta 是缺血/缺氧诱导的凋亡性心肌细胞死亡的关键因子，基于其抑制的策略可能有益于急性缺血性心脏病的治疗。
