Bowes J, Piper J, Thiemermann C
William Harvey Research Institute, St Bartholomew's and the Royal London School of Medicine and Dentistry.
Br J Pharmacol. 1998 Aug;124(8):1760-6. doi: 10.1038/sj.bjp.0702009.
Poly (ADP-ribose) synthetase (PARS) is a nuclear enzyme activated by strand breaks in DNA which are caused by reactive oxygen species (ROS). Inhibitors of PARS activity reduce the degree of reperfusion injury of the heart in vivo and in vitro. Here we investigate the role of PARS in the cell death of human cardiac myoblasts caused by hydrogen peroxide. Exposure of human cardiac myoblasts to hydrogen peroxide caused a time- and concentration-dependent reduction in mitochondrial respiration (cell injury), an increase in cell death (LDH release), as well as an increase in PARS activity. The PARS inhibitors 3-aminobenzamide (3 mM), 1,5-dehydroxyisoquinoline (300 microM) or nicotinamide (3 mM) attenuated the cell injury and death as well as the increase in PARS activity caused by hydrogen peroxide (3 mM; 4 h for cell injury/death, 60 min for PARS activity) in human cardiac myoblasts. In contrast, the inactive analogues 3-aminobenzoic acid (3 mM) or nicotinic acid (3 mM) were without effect. The iron chelator deferoxamine (1-10 mM) caused a concentration-dependent reduction in the cell injury and death caused by hydrogen peroxide in these human cardiac myoblasts. Thus, the cell injury/death caused by hydrogen peroxide in human cardiac myoblasts is secondary to the formation of hydroxyl radicals and due to an increase in PARS activity. We therefore propose that activation of PARS contributes to the cell injury/cell death associated with oxidant stress in the heart.
聚（ADP-核糖）合成酶（PARS）是一种核酶，可被活性氧（ROS）引起的DNA链断裂激活。PARS活性抑制剂可降低体内和体外心脏再灌注损伤的程度。在此，我们研究PARS在过氧化氢引起的人心脏成肌细胞死亡中的作用。将人心脏成肌细胞暴露于过氧化氢会导致线粒体呼吸（细胞损伤）呈时间和浓度依赖性降低、细胞死亡增加（乳酸脱氢酶释放）以及PARS活性增加。PARS抑制剂3-氨基苯甲酰胺（3 mM）、1,5-二羟基异喹啉（300 microM）或烟酰胺（3 mM）可减轻人心脏成肌细胞中过氧化氢（3 mM；细胞损伤/死亡作用4小时，PARS活性作用60分钟）引起的细胞损伤和死亡以及PARS活性增加。相比之下，无活性类似物3-氨基苯甲酸（3 mM）或烟酸（3 mM）则无作用。铁螯合剂去铁胺（1 - 10 mM）可使这些人心脏成肌细胞中过氧化氢引起的细胞损伤和死亡呈浓度依赖性降低。因此，过氧化氢在人心脏成肌细胞中引起的细胞损伤/死亡继发于羟自由基的形成，且是由于PARS活性增加所致。我们因此提出，PARS的激活促成了与心脏氧化应激相关的细胞损伤/细胞死亡。
