General Surgery Department, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.
Department of Pediatrics, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China.
Mol Med Rep. 2024 Apr;29(4). doi: 10.3892/mmr.2024.13188. Epub 2024 Mar 1.
Liver sinusoidal endothelial cells (LSECs) have an important role in hepatic ischemia‑reperfusion injury (I/R), but the specific molecular mechanism of action is unknown. LSEC proliferation is regulated and fenestration is maintained via the Sentrin/SUMO‑specific protease 1 (SENP1)/hypoxia‑inducible factor‑1α (HIF‑1α) signaling axis under hypoxic conditions. In the present study, a hypoxia‑reoxygenation (H‑R) injury model was established using mouse LSECs to explore the relationship between SENP1 and H‑R injury , and the specific underlying mechanism was identified, revealing new targets for the clinical attenuation of hepatic I/R injury. Following the culture of LSECs under H‑R conditions, it was demonstrated that the expression of SENP1 was upregulated by reverse transcription‑quantitative polymerase chain reaction and western blotting (WB). In addition, scanning electron microscopy indicated that fenestrae damage was increased, a Cell Counting Kit‑8 assay demonstrated that the proliferation of cells was impaired and flow cytometry showed that apoptosis was increased. After silencing SENP1 expression with short interfering RNA, the proliferation activity of LSECs decreased, the fenestrae damage increased, the apoptosis rate increased and the expression levels of SENP1, HIF‑1α, heme oxygenase and Bcl‑2 were downregulated (as demonstrated by WB), while the expression levels of apoptosis‑related proteins, cleaved‑caspase‑3 and Bax, were upregulated. Enzyme‑linked immunosorbent assay detection showed that the level of vascular endothelial growth factor in the supernatant decreased and the level of IL‑6 and TNF‑α increased. Following the administration of an HIF‑1α signaling pathway agonist, the situation was reversed. These results therefore suggested that SENP1 attenuated the reduction in proliferation, apoptosis and fenestration of LSECs observed following H‑R injury through the HIF‑1α signaling pathway. In conclusion, SENP1 may attenuate H‑R injury in LSECs in a HIF‑1α signaling pathway‑dependent manner.
肝窦内皮细胞（LSEC）在肝缺血再灌注损伤（I/R）中具有重要作用，但具体的作用机制尚不清楚。在缺氧条件下，LSEC 的增殖受到调节，窗孔通过连接酶/ SUMO-特异性蛋白酶 1（SENP1）/缺氧诱导因子-1α（HIF-1α）信号轴维持。本研究采用小鼠 LSEC 建立缺氧/复氧（H-R）损伤模型，探讨 SENP1 与 H-R 损伤的关系及其潜在的作用机制，为临床减轻肝 I/R 损伤提供新的靶点。采用 H-R 条件培养 LSEC 后，逆转录定量聚合酶链反应（RT-qPCR）和 Western blot（WB）结果均表明 SENP1 的表达上调。此外，扫描电子显微镜显示窗孔损伤增加，细胞计数试剂盒-8（CCK-8）检测结果表明细胞增殖受损，流式细胞术检测结果表明细胞凋亡增加。用小干扰 RNA（siRNA）沉默 SENP1 表达后，LSEC 的增殖活性降低，窗孔损伤增加，细胞凋亡率增加，SENP1、HIF-1α、血红素加氧酶和 Bcl-2 的表达水平下调（WB 结果），而凋亡相关蛋白 cleaved-caspase-3 和 Bax 的表达水平上调。酶联免疫吸附试验（ELISA）检测显示上清液中血管内皮生长因子（VEGF）水平降低，IL-6 和 TNF-α水平升高。给予 HIF-1α 信号通路激动剂后，上述情况得到逆转。综上所述，SENP1 可能通过 HIF-1α 信号通路减轻 LSEC 缺氧再复氧损伤导致的增殖、凋亡和窗孔减少。SENP1 可能通过 HIF-1α 信号通路减轻 LSEC 缺氧再复氧损伤导致的增殖、凋亡和窗孔减少。
