Inhibitors of poly (ADP-ribose) polymerase ameliorate myocardial reperfusion injury by modulation of activator protein-1 and neutrophil infiltration
Inhibitors of poly (ADP-ribose) polymerase ameliorate myocardial reperfusion injury by modulation of activator protein-1 and neutrophil infiltration
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DOI：
10.1097/01.shk.0000151026.30624.ef
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发表时间：
2005-03-01
期刊：
影响因子：
3.1
通讯作者：
Zingarelli, B
中科院分区：
文献类型：
--
作者：
Kaplan, J;O'Connor, M;Zingarelli, B
在心肌再灌注损伤过程中，氧化应激诱导DNA损伤和核酶聚（ADP-核糖）聚合酶-1（PARP-1）的激活，导致心血管功能障碍。在这项研究中，我们研究了两种结构无关的PARP-1，3-氨基苯甲酰胺（3-AB）和1，5-二羟基异喹啉（1，5-DIQ）的选择性抑制剂的生物学效应和分子机制，在体内模型的心肌缺血和再灌注。雄性Wistar大鼠进行30分钟的闭塞，然后再灌注（长达24小时）的左前降支冠状动脉。在溶剂处理的大鼠中，缺血和再灌注诱导广泛的心肌损伤和显著的中性粒细胞浸润（如髓过氧化物酶活性所示）。Caspase 3在再灌注后15 ~ 30 min内激活最强，提示细胞凋亡的发生。这些炎症事件与再灌注心脏中转录因子激活蛋白-1（AP-1）的激活有关。用PARP-1抑制剂3-AB或1，5-DIQ处理大鼠，可减少心肌损伤、中性粒细胞浸润和半胱天冬酶活化。这种心脏保护作用与AP-1激活的减少有关。此外，在体外的姜黄素刺激的人内皮细胞，细胞间粘附分子1，血管细胞粘附分子1，P-和E-选择素的表达显着减少治疗3-AB或1，5-DIQ。相反，在体内或体外处理与烟酸，PARP抑制剂的化学类似物，缺乏抑制PARP-1的催化活性的能力，不能提供任何保护作用，并防止AP-1的激活。我们的数据表明，抑制PARP-1的催化活性可以通过调节应激诱导的信号转导途径提供心脏保护。
During myocardial reperfusion injury, oxidative stress induces DNA damage and activation of the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1), resulting in cardiovascular dysfunction. In this study, we investigated the biological effects and the molecular mechanisms of two structurally unrelated selective inhibitors of PARP-1, 3-aminobenzamide (3-AB) and 1,5-dihydroxyisoquinoline (1,5-DIQ), in an in vivo model of myocardial ischemia and reperfusion. Male Wistar rats were subjected to 30 min of occlusion followed by reperfusion (up to 24 h) of the left anterior descending coronary artery. In vehicle-treated rats, ischemia and reperfusion induced extensive myocardial damage and marked neutrophil infiltration (as indicated by myeloperoxidase activity). Caspase 3 was maximally activated within 15 to 30 min after reperfusion, suggesting the occurrence of apoptosis. These inflammatory events were associated with activation of the transcription factor activator protein-1 (AP-1) in the reperfused hearts. Treatment of the rats with the PARP-1 inhibitors, 3-AB or 1,5-DIQ, reduced myocardial damage, neutrophil infiltration, and caspase activation. This cardioprotection was associated with reduction of AP-1 activation. Furthermore, in in vitro cytokine-stimulated human endothelial cells, expression of intercellular adhesion molecule 1, vascular cellular adhesion molecule 1, and P- and E-selectin was significantly reduced by treatment with 3-AB or 1,5-DIQ. On the contrary, in vivo or in vitro treatment with nicotinic acid, a chemical analogue of PARP inhibitors, which lacks the ability to inhibit the catalytic activity of PARP-1, was unable to afford any protective effect and to prevent activation of AP-1. Our data demonstrate that inhibition of catalytic activity of PARP-1 may provide cardioprotection by regulating stress-induced signal transduction pathways.