Department of Endocrinology, Shanghai Children's Hospital, Shanghai Jiaotong University, Shanghai, China.
Department of Emergency, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Exp Cell Res. 2022 Dec 15;421(2):113400. doi: 10.1016/j.yexcr.2022.113400. Epub 2022 Oct 23.
Loss of poly (ADP-ribose) polymerase-1 (PARP-1) has been found to slow the progression of diabetes and diabetic angiopathy. In our study, we found bidirectional regulation of PARP-1 in high glucose induced endothelial injury, which promoting repair at the early stage of injury and inhibiting repair at the late stage of injury. To further investigate the mechanism of PARP-1 regulation, we first examined the expression of PARP-1 in aortic tissues and cultured cells at early, middle, and late stages of injury, PARP-1 expression was significantly greater than that of control group. Overexpression of PARP-1 in HUVECs significantly reduced the number of apoptotic cells 12 h after high glucose injury, while reducing the level of reactive oxygen species (ROS)/malondialdehyde (MDA)/inducible nitric oxide synthase (iNOS), increasing the level of endothelial nitric oxide synthase (eNOS); however, when the injury extended to 3 days, the number of apoptosis in HUVECs overexpressing PARP-1 was significantly higher than that in the injury group, and the level of ROS/MDA/iNOS was significantly higher, while the secretion of eNOS was significantly lower. Similarly, PARP-1 inhibitors aggravate early damage and inhibit late damage. We found that PARP-1 promoted the activation of P53 and P53R2 in endothelial cells after 12 h of injury, and PARP-1 promoted the activation of P53 and caspas3 in endothelial cells after 3 days of injury. Therefore, we suggest that PARP-1 plays a dual regulatory role in promoting repair or aggravating injury.
聚 ADP-核糖聚合酶 1（PARP-1）的缺失已被发现可减缓糖尿病和糖尿病血管病变的进展。在我们的研究中，我们发现高葡萄糖诱导的内皮损伤中存在 PARP-1 的双向调节，即在损伤的早期促进修复，而在损伤的晚期抑制修复。为了进一步研究 PARP-1 调节的机制，我们首先检查了损伤早期、中期和晚期主动脉组织和培养细胞中 PARP-1 的表达，PARP-1 的表达明显高于对照组。在 HUVECs 中过表达 PARP-1 可显著减少高葡萄糖损伤后 12 小时的凋亡细胞数量，同时降低活性氧（ROS）/丙二醛（MDA）/诱导型一氧化氮合酶（iNOS）水平，增加内皮型一氧化氮合酶（eNOS）水平；然而，当损伤持续 3 天时，过表达 PARP-1 的 HUVECs 中的凋亡数量明显高于损伤组，并且 ROS/MDA/iNOS 水平明显升高，而 eNOS 的分泌明显降低。同样，PARP-1 抑制剂加重早期损伤并抑制晚期损伤。我们发现，PARP-1 在损伤后 12 小时促进内皮细胞中 P53 和 P53R2 的激活，在损伤后 3 天促进内皮细胞中 P53 和 caspas3 的激活。因此，我们认为 PARP-1 在促进修复或加重损伤方面发挥双重调节作用。
