Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, Pécs, Hungary.
Department of Anatomy, MTA-PTE PACAP Research Group, University of Pécs Medical School, Pécs, Hungary.
Invest Ophthalmol Vis Sci. 2019 Apr 1;60(5):1478-1490. doi: 10.1167/iovs.18-25936.
In the eye, chronic hypoxia/reoxygenation (H/R) contributes to the development of a number of ocular disorders. H/R induces the production of reactive oxygen species (ROS), leading to poly(ADP-ribose) polymerase-1 (PARP1) activation that promotes inflammation, cell death, and disease progression. Here, we analyzed the protective effects of the PARP1 inhibitor olaparib in H/R-induced retina injury and investigated the signaling mechanisms involved.
A rat retinal H/R model was used to detect histologic and biochemical changes in the retina.
H/R induced reductions in the thickness of most retinal layers, which were prevented by olaparib. Furthermore, H/R caused increased levels of Akt and glycogen synthase kinase-3β phosphorylation, which were further increased by olaparib, contributing to retina protection. By contrast, H/R-induced c-Jun N-terminal kinase and p38 mitogen-activated protein kinases (MAPK) phosphorylation and activation were reduced by olaparib, via mitogen-activated protein kinase phosphatase 1 (MKP-1) expression. In addition, H/R-induced hypoxia-inducible factor 1α (HIF1α) levels were decreased by olaparib, which possibly contributed to reduced VEGF expression. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression was slightly increased by H/R and was further activated by olaparib. Nuclear factor-κB (NFκB) was also activated by H/R through phosphorylation (Ser536) and acetylation (Lys310) of the p65 subunit, although this was significantly reduced by olaparib.
Olaparib reduced H/R-induced degenerative changes in retinal morphology. The protective mechanisms of olaparib most probably involved Nrf2 activation and ROS reduction, as well as normalization of HIF1α and related VEGF expression. In addition, olaparib reduced inflammation by NFκB dephosphorylation/inactivation, possibly via the PARP1 inhibition-MKP-1 activation-p38 MAPK inhibition pathway. PARP inhibitors represent potential therapeutics in H/R-induced retinal disease.
在眼睛中，慢性缺氧/复氧（H/R）导致许多眼部疾病的发展。H/R 诱导活性氧（ROS）的产生，导致多聚（ADP-核糖）聚合酶-1（PARP1）的激活，从而促进炎症、细胞死亡和疾病进展。在这里，我们分析了 PARP1 抑制剂奥拉帕利在 H/R 诱导的视网膜损伤中的保护作用，并研究了涉及的信号机制。
使用大鼠视网膜 H/R 模型来检测视网膜中的组织学和生化变化。
H/R 诱导大多数视网膜层厚度降低，奥拉帕利可预防这种降低。此外，H/R 引起 Akt 和糖原合酶激酶-3β磷酸化水平升高，奥拉帕利进一步增加这些水平，有助于保护视网膜。相反，奥拉帕利通过丝裂原激活蛋白激酶磷酸酶 1（MKP-1）的表达，减少 H/R 诱导的 c-Jun N 末端激酶和 p38 丝裂原激活蛋白激酶（MAPK）磷酸化和激活。此外，奥拉帕利降低 H/R 诱导的缺氧诱导因子 1α（HIF1α）水平，这可能导致 VEGF 表达减少。核因子（红系衍生 2）样 2（Nrf2）的表达在 H/R 后略有增加，并且被奥拉帕利进一步激活。核因子-κB（NFκB）也通过 p65 亚基的磷酸化（Ser536）和乙酰化（Lys310）被 H/R 激活，尽管这被奥拉帕利显著减少。
奥拉帕利减少了 H/R 诱导的视网膜形态学退行性变化。奥拉帕利的保护机制可能涉及 Nrf2 激活和 ROS 减少，以及 HIF1α 和相关 VEGF 表达的正常化。此外，奥拉帕利通过 NFκB 去磷酸化/失活减少炎症，可能通过 PARP1 抑制-MKP-1 激活-p38 MAPK 抑制途径。PARP 抑制剂可能是 H/R 诱导的视网膜疾病的潜在治疗药物。
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