Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Centre for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
Int Immunopharmacol. 2021 May;94:107507. doi: 10.1016/j.intimp.2021.107507. Epub 2021 Feb 28.
Hemorrhagic transformation (HT) is a frequent complication of ischemic stroke after thrombolytic therapy and seriously affects the prognosis of stroke. Due to the limited therapeutic window and hemorrhagic complications, tissue plasminogen activator (t-PA) is underutilized in acute ischemic stroke. Currently, there are no clinically effective drugs to decrease the incidence of t-PA-induced HT. Hypoxia-inducible factor 1 (HIF-1) is an important transcription factor that maintains oxygen homeostasis and mediates neuroinflammation under hypoxia. However, the effect of HIF-1 on t-PA-induced HT is not clear. The aim of this study was to investigate the role of HIF-1 in t-PA-induced HT by applying YC-1, an inhibitor of HIF-1. In the present study, we found that HIF-1 expression was significantly increased in ischemic brain tissue after delayed t-PA treatment and was mainly localized in neurons and endothelial cells. Inhibition of HIF-1 by YC-1 improved infarct volume and neurological deficits. YC-1 inhibited matrix metalloproteinase protein expression, increased tight junction protein expression, and ameliorated BBB disruption and the occurrence of HT. Furthermore, YC-1 suppressed the release of inflammatory factors, neutrophil infiltration and the activation of the HMGB1/TLR4/NF-κB signaling pathway. These results demonstrated that inhibition of HIF-1 could protect BBB integrity by suppressing HMGB1/TLR4/NF-κB-mediated neutrophil infiltration, thereby reducing the risk of t-PA-induced HT. Thus, HIF-1 may be a potential therapeutic target for t-PA-induced HT.
出血转化（HT）是缺血性卒中溶栓治疗后的常见并发症，严重影响卒中预后。由于治疗窗口有限和出血并发症，组织型纤溶酶原激活剂（t-PA）在急性缺血性卒中中的应用受到限制。目前，尚无临床有效的药物可降低 t-PA 诱导的 HT 发生率。缺氧诱导因子 1（HIF-1）是一种重要的转录因子，在缺氧下可维持氧平衡并介导神经炎症。然而，HIF-1 对 t-PA 诱导的 HT 的影响尚不清楚。本研究旨在通过应用 HIF-1 抑制剂 YC-1 来研究 HIF-1 在 t-PA 诱导的 HT 中的作用。本研究发现，延迟 t-PA 治疗后缺血性脑组织中 HIF-1 表达显著增加，主要定位于神经元和内皮细胞。YC-1 抑制 HIF-1 可改善梗死体积和神经功能缺损。YC-1 抑制基质金属蛋白酶蛋白表达，增加紧密连接蛋白表达，改善 BBB 破坏和 HT 的发生。此外，YC-1 抑制炎症因子的释放、中性粒细胞浸润和 HMGB1/TLR4/NF-κB 信号通路的激活。这些结果表明，抑制 HIF-1 可通过抑制 HMGB1/TLR4/NF-κB 介导的中性粒细胞浸润来保护 BBB 完整性，从而降低 t-PA 诱导的 HT 风险。因此，HIF-1 可能是 t-PA 诱导的 HT 的潜在治疗靶点。
