Differential regulation of activator protein-1 and heat shock factor-1 in myocardial ischemia and reperfusion injury: role of poly(ADP-ribose) polymerase-1.
Differential regulation of activator protein-1 and heat shock factor-1 in myocardial ischemia and reperfusion injury: role of poly(ADP-ribose) polymerase-1.
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DOI：
10.1152/ajpheart.00953.2003
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发表时间：
2004-04
期刊：
影响因子：
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通讯作者：
B. Zingarelli;P. Hake;M. O’connor;A. Denenberg;H. Wong;S. Kong;B. Aronow
中科院分区：
文献类型：
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作者：
B. Zingarelli;P. Hake;M. O’connor;A. Denenberg;H. Wong;S. Kong;B. Aronow
聚（adp -核糖）聚合酶-1 （PARP-1）是一种响应DNA链断裂而激活的核酶，与心肌再灌注损伤的细胞功能障碍有关。PARP-1也被证明参与基因表达的转录和调控。在本研究中，我们研究了PARP-1在心肌再灌注损伤中激活蛋白-1 （AP-1）和热休克因子-1 （HSF-1）信号转导通路中的作用。与野生型小鼠相比，PARP-1基因缺陷小鼠（PARP-1（-/-）小鼠）在冠状动脉左前降支闭塞和再灌注后心肌损伤显著减少。这种心脏保护作用与JNK磷酸化活性的降低以及随后信号转导因子AP-1的DNA结合减少有关。相反，在PARP-1（-/-）小鼠中，与野生型小鼠相比，HSF-1的DNA结合增强，并与心脏保护性热休克蛋白（HSP）70显著增加相关。微阵列分析显示，在PARP-1（-/-）小鼠中，促炎介质和热休克蛋白的几个ap -1依赖性基因的表达发生了改变。这些数据提示PARP-1可能通过增强AP-1激活、抑制HSF-1激活和HSP70表达而在再灌注损伤中发挥病理作用。
Poly(ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme activated in response to DNA strand breaks, has been implicated in cell dysfunction in myocardial reperfusion injury. PARP-1 has also been shown to participate in transcription and regulation of gene expression. In this study, we investigated the role of PARP-1 on the signal transduction pathway of activator protein-1 (AP-1) and heat shock factor-1 (HSF-1) in myocardial reperfusion injury. Mice genetically deficient of PARP-1 (PARP-1(-/-) mice) exhibited a significant reduction of myocardial damage after occlusion and reperfusion of the left anterior descending branch of the coronary artery compared with their wild-type littermates. This cardioprotection was associated with a reduction of the phosphorylative activity of JNK and, subsequently, reduction of the DNA binding of the signal transduction factor AP-1. On the contrary, in PARP-1(-/-) mice, DNA binding of HSF-1 was enhanced and was associated with a significant increase of the cardioprotective heat shock protein (HSP)70 compared with wild-type mice. Microarray analysis revealed that expression of several AP-1-dependent genes of proinflammatory mediators and HSPs was altered in PARP-1(-/-) mice. The data indicate that PARP-1 may exert a pathological role in reperfusion injury by functioning as an enhancing factor of AP-1 activation and as a repressing factor of HSF-1 activation and HSP70 expression.