Development of therapeutic agents for ischemia/reperfusion injury utilizing a novel regulatory mechanism of Parp1

PARP1是一种重要的酶，参与脑梗塞、心肌梗死和多器官移植后血流恢复的I/R损伤等多种病理生理现象。I/R诱导的PARP1过度激活是通过产生活性氧介导的，并参与了NF-κB的反式激活。出于这些原因，PARP1是预防I/R损伤的战略的一个有吸引力的目标。由于我们发现MDM2抑制剂Nutlin-3a可以降低培养细胞中PARP1的蛋白水平，因此我们研究了PARP1在开发缺血/再灌注损伤治疗药物方面的新的调节机制。结果表明，Nutlin-3a及其类似物Caylin-2以P53依赖的方式诱导PARP1蛋白酶体降解，PARP1表达下调是可逆的，并伴随着炎症反应。为了防止I/R损伤，我们的结果支持P53诱导的顺式咪唑啉化合物Nutlin-3a及其类似物作为PARP1抑制剂的可用性。

PARP1 is an important enzyme involved in various patho-physiological phenomena such as ischemia/reperfusion (I/R) injury, which occurs when blood flow is restored after cerebral infarction, myocardial infarction and transplantation of various organs. I/R-induced PARP1 over-activation is mediated by production of reactive oxygen species and is involved in NF-κB transactivation. For these reasons, PARP1 is an attractive target for strategies to protect against I/R injury. Because we found that Nutlin-3a, an MDM2 inhibitor, treatment reduces the protein levels of PARP1 in culture cells, we investigated the novel regulatorymechanism of PARP1 for development of therapeutic agents for ischemia/reperfusion injury. Consequently we obtained the results that Nutlin-3a and its analogue Caylin-2 treatment induce proteasomal degradation of PARP1 in a p53-dependent manner, and the down-regulation of PARP1 is reversible and accompanied with an inflammatory response. For protection against I/R injury, our results support the usability of the p53 inducible cis-imidazoline compounds, Nutlin-3a and its analogs, as PARP1 inhibitors.