Activation of poly(ADP-ribose) polymerase contributes to development of doxorubicin-induced heart failure
Activation of poly(ADP-ribose) polymerase contributes to development of doxorubicin-induced heart failure
复制标题
DOI：
10.1124/jpet.300.3.862
复制
发表时间：
2002-03-01
影响因子：
3.5
通讯作者：
Szabó, C
中科院分区：
文献类型：
--
作者：
Pacher, P;Liaudet, L;Szabó, C
核酶多聚腺苷二磷酸核糖聚合酶(PARP)被氧化剂介导的DNA损伤激活，是氧化应激条件下细胞功能障碍和组织损伤的重要途径。氧化应激增加是阿霉素(DOX)心脏毒性的一个主要因素，DOX是一种广泛使用的抗肿瘤蒽环类抗生素。因此，我们推测PARP的激活可能参与了DOX诱导的心脏毒性。采用PARP-1抑制的双重方法，通过基因缺失或用菲的PARP抑制剂PJ34进行药物抑制，我们现在证明了PARP在DOX PARP-1+/+和PARP-1-/-小鼠单次注射DOX(25 mg/kg i.p)引起的心功能障碍中的作用。给药5天后，PARP-1+/+组小鼠左心功能显著降低，但PARP-1-/-组仅有较小程度的降低。用PJ34或赋形剂处理的BALB/c小鼠也进行了类似的实验。使用PJ34的治疗显著改善了心功能障碍，提高了动物的存活率。此外，PJ34还能显着降低DOX引起的血清乳酸脱氢酶和心肌肌酸激酶活性的升高，但不能显着降低心脏金属蛋白酶的活性。因此，PARP激活有助于DOX的心脏毒性，PARP抑制剂可能对与DOX治疗相关的严重心脏并发症的发生起到保护作用。
Activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) by oxidant-mediated DNA damage is an important pathway of cell dysfunction and tissue injury in conditions associated with oxidative stress. Increased oxidative stress is a major factor implicated in the cardiotoxicity of doxorubicin (DOX), a widely used antitumor anthracycline antibiotic. Thus, we hypothesized that the activation of PARP may contribute to the DOX-induced cardiotoxicity. Using a dual approach of PARP-1 suppression, by genetic deletion or pharmacological inhibition with the phenanthridinone PARP inhibitor PJ34, we now demonstrate the role of PARP in the development of cardiac dysfunction induced by DOX PARP-1+/+ and PARP-1-/- mice received a single injection of DOX (25 mg/kg i.p). Five days after DOX administration, left ventricular performance was significantly depressed in PARP-1+/+ mice, but only to a smaller extent in PARP-1-/- ones. Similar experiments were conducted in BALB/c mice treated with PJ34 or vehicle. Treatment with a PJ34 significantly improved cardiac dysfunction and increased the survival of the animals. In addition PJ34 significantly reduced the DOX-induced increase in the serum lactate dehydrogenase and creatine kinase activities but not metalloproteinase activation in the heart. Thus, PARP activation contributes to the cardiotoxicity of DOX PARP inhibitors may exert protective effects against the development of severe cardiac, complications associated with the DOX treatment.