Endothelial dysfunction is critical in the pulmonary vasculature during pulmonary hypertension (PH). Moreover, in PH, increased inflammation and oxidative/nitrosative stress cause DNA damage, activating poly (ADP-ribose) polymerase-1 (PARP-1). Meloche et al. (2014) and our previous research have shown that inhibiting PARP-1 is protective in PH and associated RV hypertrophy. However, the role of PARP-1 in pulmonary arterial endothelial dysfunction has not been explored completely. Therefore, the current study aims to investigate the involvement of PARP-1 in endothelial dysfunction associated with PH. Hypoxia (1% O2) was used to induce a PH-like phenotype in human pulmonary artery endothelial cells (HPAECs), and PARP-1 inhibition was achieved via siRNA (60 nM). For the in vivo study, male Sprague Dawley rats were administered monocrotaline (MCT; 60 mg/kg, SC, once) to induce PH, and 1, 5-isoquinolinediol (ISO; 3 mg/kg) was administered daily intraperitoneally to inhibit PARP-1. PARP-1 inhibition decreased proliferation and inflammation, as well as improved mitochondrial dysfunction in hypoxic HPAECs. Furthermore, PARP-1 inhibition also promoted apoptosis by increasing DNA damage in hypoxic HPAECs. In addition, inhibition of PARP-1 reduced cell migration, VEGF expression, and tubule formation in hypoxic HPAECs. In in vivo studies, PARP-1 inhibition by ISO significantly decreased the RVP and RVH as well as improved endothelial function by increasing the pulmonary vascular reactivity and expression of p-eNOS in MCT-treated rats.

内皮功能障碍在肺动脉高压 (PH) 期间对肺血管系统至关重要。此外，在 PH 中，炎症增加和氧化/亚硝化应激会导致 DNA 损伤，从而激活聚（ADP-核糖）聚合酶-1（PARP-1）。梅洛切等人。(2014) 和我们之前的研究表明，抑制 PARP-1 对 PH 和相关的 RV 肥大具有保护作用。然而，PARP-1 在肺动脉内皮功能障碍中的作用尚未完全探索。因此，本研究旨在探讨 PARP-1 在与 PH 相关的内皮功能障碍中的作用。缺氧(1% O2) 用于在人肺动脉内皮细胞中诱导 PH 样表型(HPAECs)，PARP-1 抑制是通过 siRNA (60 nM) 实现的。对于体内研究，对雄性Sprague Dawley 大鼠施用野百合碱（MCT；60 mg/kg，SC，一次）以诱导 PH，并且每天腹膜内施用 1, 5-异喹啉二醇（ISO；3 mg/kg）以抑制 PARP -1。PARP-1 抑制可减少增殖和炎症，并改善缺氧 HPAEC 中的线粒体功能障碍。此外，PARP-1 抑制还通过增加缺氧 HPAEC 中的 DNA 损伤来促进细胞凋亡。此外，抑制 PARP-1 可减少缺氧 HPAEC 中的细胞迁移、VEGF 表达和小管形成。在体内研究中，ISO 对 PARP-1 的抑制显着降低了 RVP 和RVH，并改善了通过增加MCT 治疗大鼠的肺血管反应性和 p-eNOS 表达来改善内皮功能。