GATA-4 regulation of myocardial survival in the preconditioned heart.
GATA-4 regulation of myocardial survival in the preconditioned heart.
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DOI：
10.1016/j.yjmcc.2004.09.009
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发表时间：
2004-12
影响因子：
5
通讯作者：
Yuichiro J. Suzuki;H. Nagase;R. Day;D. Das
中科院分区：
文献类型：
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作者：
Yuichiro J. Suzuki;H. Nagase;R. Day;D. Das
最近的研究发现，加塔-4是一种应激反应转录因子，在心肌细胞中发挥细胞存活信号的作用。本研究旨在检测缺血预处理（PC）和缺血/再灌注（I/R）是否对加塔-4有调节作用。用Krebs-Henseleit碳酸氢盐缓冲液灌流离体大鼠心脏，以5 min缺血和10 min再灌注为4个循环，诱发PC。然后对一些心脏进行30 min缺血，随后2 h再灌注。与对照组相比，PC增加了加塔-4的DNA结合活性，而I/R下调了加塔-4的表达。激活与通过乙酰化对加塔-4进行的翻译后修饰相关。由于一氧化氮（NO）可能参与PC和I/R，我们研究了NO是否可以调节HL-1心肌细胞的加塔-4。NO供体硝普钠（SNP）下调加塔活性和加塔-4 mRNA表达。我们克隆了人加塔-4基因的5′侧翼区，发现该区域控制的荧光素酶活性也被NO抑制，蛋白激酶G（PKG）抑制剂KT 5823抑制SNP诱导的加塔-4下调，而YC-1（鸟苷酸环化酶激活剂）和二丁酰cGMP（PKG激活剂）下调加塔-4。因此，加塔-4受PC、I/R和NO的调节，并可能调节心肌细胞的存活和凋亡。
Recent studies identified that GATA-4 is a stress responsive transcription factor and can exert cell survival signaling in cardiac myocytes. The present study was designed to examine whether GATA-4 is modulated by ischemic preconditioning (PC), and ischemia/reperfusion (I/R). PC of isolated rat hearts was elicited by perfusing with Krebs–Henseleit bicarbonate buffer with four cyclic episodes of 5 min ischemia and 10 min reperfusion. Some hearts were then subjected to 30 min ischemia followed by 2 h reperfusion. PC increased the DNA binding activity of GATA-4 compared to control, while I/R downregulated GATA-4 expression. Activation was associated with post-translational modifications of GATA-4 via acetylation. As nitric oxide (NO) may be involved in PC and I/R, we examined whether NO could modulate GATA-4 in HL-1 cardiac muscle cells. An NO donor, sodium nitroprusside (SNP), downregulated GATA activity and GATA-4 mRNA expression. We cloned the 5′-flanking region of human GATA-4 gene and found that the luciferase activity controlled by this region was also suppressed by NO. A protein kinase G (PKG) inhibitor KT5823 inhibited SNP-induced downregulation of GATA-4, while YC-1 (guanylyl cyclase activator) and dibutyryl cGMP (PKG activator) downregulated GATA-4. Thus, GATA-4 is modulated by PC, I/R and NO, and might regulate cardiac myocyte survival and apoptosis.