Sasaki H, Galang N, Maulik N
Department of Surgery, University of Connecticut School of Medicine, Farmington 06030-1110, USA.
Antioxid Redox Signal. 1999 Fall;1(3):317-24. doi: 10.1089/ars.1999.1.3-317.
Two redox-sensitive transcription factors, AP-1 and NF-kappaB, have been implicated in the regulation of apoptosis induced by myocardial ischemia and reperfusion. Hearts adapted to ischemic stress by cyclic episodes of short durations of ischemia and reperfusion attenuate apoptotic cell death. This study was designed to examine the pattern of expression of these transcription factors and the redox sensitive transacting molecule, AP-1, NF-kappaB, and- Bcl-2, during ischemia/ reperfusion and myocardial adaptation to ischemia. NF-kappaB binding activity was low in nonischemic control heart. Fifteen minutes of ischemia resulted in translocation of NF-kappaB from cytosol to nucleus followed by activation. The binding activity of NF-kappaB was further enhanced after 60 min of ischemia. An even higher degree of NF-kappaB binding was noticed in the ischemically adapted myocardium. In contrast, AP-1 binding activity was highest for the hearts subjected to 15 min of ischemia followed by 2 hr of reperfusion. AP-1 binding was higher in the ischemically adapted heart as compared to the control. The Bcl-2 gene, which was found to be present in the control hearts, had lowered expression after 15 min of ischemia and 2 hr of reperfusion. Significant upregulation of Bcl-2 mRNA was noticed in the ischemically adapted hearts. Apoptotic cardiomyocytes were found only in the hearts that were reperfused for at least 90 min. No apoptosis occurred in hearts subjected up to 1 hr of ischemia or ischemic adaptation. Prolonged reperfusion, and not ischemia up to 1 hr, can induce cardiomyocyte apoptosis. In concert, ischemic/reperfusion increases the nuclear binding of both AP-1 and NF-kappaB, but downregulates Bcl-2 gene. Ischemic adaptation attenuates apoptotic cell death, further increases NF-kappaB binding activity and Bcl-2 gene induction, but reduces AP-1 binding activity. These results suggest that AP-1, NF-kappaB, and Bcl-2 are differentially regulated by ischemia/reperfusion and ischemic adaptation.
两种氧化还原敏感型转录因子，即活化蛋白-1（AP-1）和核因子-κB（NF-κB），参与了心肌缺血再灌注诱导的细胞凋亡调控。通过短暂的缺血和再灌注循环发作使心脏适应缺血应激，可减轻凋亡性细胞死亡。本研究旨在检测这些转录因子以及氧化还原敏感型反式作用分子AP-1、NF-κB和Bcl-2在缺血/再灌注及心肌对缺血的适应过程中的表达模式。在非缺血对照心脏中，NF-κB结合活性较低。缺血15分钟导致NF-κB从胞质溶胶转位至细胞核，随后被激活。缺血60分钟后，NF-κB的结合活性进一步增强。在缺血适应的心肌中，观察到更高程度的NF-κB结合。相比之下，对于经历15分钟缺血后再灌注2小时的心脏，AP-1结合活性最高。与对照相比，缺血适应心脏中的AP-1结合更高。发现对照心脏中存在的Bcl-2基因，在缺血15分钟和再灌注2小时后表达降低。在缺血适应心脏中，观察到Bcl-2 mRNA显著上调。仅在再灌注至少90分钟的心脏中发现凋亡心肌细胞。在缺血长达1小时或缺血适应的心脏中未发生凋亡。延长再灌注而非长达1小时的缺血可诱导心肌细胞凋亡。一致的是，缺血/再灌注增加了AP-1和NF-κB两者的核结合，但下调了Bcl-2基因。缺血适应减轻凋亡性细胞死亡，进一步增加NF-κB结合活性和Bcl-2基因诱导，但降低AP-1结合活性。这些结果表明，AP-1、NF-κB和Bcl-2受缺血/再灌注和缺血适应的差异调节。
