Department of Vascular Surgery, China-Japan Union Hospital of Jilin University, Changchun, China.
Ward 4 of Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China.
Life Sci. 2021 Feb 15;267:118942. doi: 10.1016/j.lfs.2020.118942. Epub 2020 Dec 29.
Intracerebral hemorrhage (ICH) induces serious neuroinflammation and damage of blood-brain barrier. We aim to investigate the role of brown fat enriched lncRNA 1 (Blnc1) in the development of ICH in mice.
An ICH model was established with autologous blood injection in C57BL/6 mice, and Blnc1 siRNA was injected intracranially. Blnc1 levels were detected and brain injury was evaluated at day 3. Primary brain microvascular endothelial cells (BMVECs) were isolated from new born mice and gain- and loss-of-function experiments were performed to investigate the role of Blnc1. Then, ICH cell model was established by treating BMVECs with oxygen and glucose deprivation (OGD) plus hemin, and Blnc1 siRNA was transfected into the cells. BMVEC functions, including viability, invasion, apoptosis, permeability and secretion of inflammatory cytokines were analyzed.
Blnc1 was upregulated in perihematomal edema, hematoma and microvessel in the brain of ICH mice. Blnc1 negatively regulated viability and migration, and facilitated apoptosis, permeability and inflammatory cytokine secretion in BMVECs. Silencing Blnc1 restrained OGD plus hemin-caused reduction of BMVEC viability and migration and the induction of apoptosis, permeability and inflammation response, and suppressed PPAR-γ/SIRT6-mediated FoxO3 activation, which could be reversed by T0070907 (PPAR-γ inhibitor). Downregulation of Blnc1 ameliorated ICH-induced nerve injury, brain edema, blood brain barrier destruction, inflammation response and hematoma. Moreover, Blnc1 levels were positively correlated with PPAR-γ levels, and Blnc1 interference suppressed PPAR-γ/SIRT6-mediated activation of FoxO3 signaling in ICH mice.
Silencing Blnc1 alleviated nerve injury and inflammatory response caused by ICH through activating PPAR-γ/SIRT6/FoxO3 pathway.
脑出血（ICH）可诱导严重的神经炎症和血脑屏障损伤。本研究旨在探讨富含棕色脂肪的长链非编码 RNA 1（Blnc1）在小鼠 ICH 发展中的作用。
采用自体血注入法建立 C57BL/6 小鼠 ICH 模型，并进行脑内 Blnc1 siRNA 注射。第 3 天检测 Blnc1 水平并评估脑损伤。从小鼠新生脑中分离原代脑微血管内皮细胞（BMVECs），并进行 gain-和 loss-of-function 实验以研究 Blnc1 的作用。然后，用氧葡萄糖剥夺（OGD）加血红素处理 BMVECs 建立 ICH 细胞模型，并转染 Blnc1 siRNA。分析 BMVEC 功能，包括活力、侵袭、凋亡、通透性和炎症细胞因子分泌。
Blnc1 在 ICH 小鼠血肿周围水肿、血肿和微血管中上调。Blnc1 负调控 BMVECs 的活力和迁移，并促进 BMVECs 的凋亡、通透性和炎症因子分泌。沉默 Blnc1 可抑制 OGD 加血红素引起的 BMVEC 活力和迁移降低以及诱导的凋亡、通透性和炎症反应，并抑制 PPAR-γ/SIRT6 介导的 FoxO3 激活，此作用可被 T0070907（PPAR-γ 抑制剂）逆转。下调 Blnc1 可改善 ICH 引起的神经损伤、脑水肿、血脑屏障破坏、炎症反应和血肿。此外，Blnc1 水平与 PPAR-γ 水平呈正相关，Blnc1 干扰可抑制 ICH 小鼠中 PPAR-γ/SIRT6 介导的 FoxO3 信号转导的激活。
沉默 Blnc1 通过激活 PPAR-γ/SIRT6/FoxO3 通路减轻 ICH 引起的神经损伤和炎症反应。
