Park Chan Sol, Lee Jee Youn, Seo Kyung Jin, Kim In Yi, Ju Bong Gun, Yune Tae Young
Age-Related and Brain Diseases Research Center, Kyung Hee University, Seoul, 02447, Republic of Korea.
Department of Biomedical Science, Kyung Hee University, Seoul, 02447, Republic of Korea.
Mol Neurobiol. 2024 Feb;61(2):662-677. doi: 10.1007/s12035-023-03617-z. Epub 2023 Sep 1.
After spinal cord injury (SCI), secondary injuries including blood cells infiltration followed by the production of inflammatory mediators are led by blood-spinal cord barrier (BSCB) breakdown. Therefore, preventing BSCB damage could alleviate the secondary injury progresses after SCI. Recently, we reported that transient receptor potential melastatin 7 channel (TRPM7) expression is increased in vascular endothelial cells after injury and thereby mediates BSCB disruption. However, the mechanism by which TRPM7 regulates BSCB disruption has not been examined yet. In current research, we show that TRPM7 mediates BSCB disruption via mammalian target of rapamycin (mTOR) pathway after SCI in rats. After contusion injury at T9 level of spinal cord, mTOR pathway was activated in the endothelial cells of blood vessels and TRPM7 was involved in the activation of mTOR pathway. BSCB disruption, MMP-2/9 activation, and blood cell infiltration after injury were alleviated by rapamycin, a mTOR signaling inhibitor. Rapamycin also conserved the level of tight junction proteins, which were decreased after SCI. Furthermore, mTOR pathway regulated the expression and activation of histone H3K27 demethylase JMJD3, known as a key epigenetic regulator mediating BSCB damage after SCI. In addition, rapamycin inhibited JMJD3 expression, the loss of tight junction molecules, and MMP-2/9 expression in bEnd.3, a brain endothelial cell line, after oxygen-glucose deprivation/reoxygenation. Thus, our results suggest that TRPM7 contributes to the BSCB disruption by regulating JMJD3 expression through the mTOR pathway after SCI.
脊髓损伤（SCI）后，血脊髓屏障（BSCB）破坏会引发包括血细胞浸润以及随后炎症介质产生在内的继发性损伤。因此，预防BSCB损伤可减轻SCI后的继发性损伤进展。最近，我们报道瞬时受体电位香草酸亚型7通道（TRPM7）在损伤后血管内皮细胞中的表达增加，从而介导BSCB破坏。然而，TRPM7调节BSCB破坏的机制尚未得到研究。在当前研究中，我们表明TRPM7在大鼠SCI后通过雷帕霉素靶蛋白（mTOR）途径介导BSCB破坏。在脊髓T9水平挫伤损伤后，血管内皮细胞中的mTOR途径被激活，且TRPM7参与了mTOR途径的激活。雷帕霉素（一种mTOR信号抑制剂）减轻了损伤后的BSCB破坏、MMP-2/9激活和血细胞浸润。雷帕霉素还维持了紧密连接蛋白的水平，该水平在SCI后降低。此外，mTOR途径调节组蛋白H3K27去甲基化酶JMJD3的表达和激活，JMJD3是介导SCI后BSCB损伤的关键表观遗传调节因子。另外，在氧糖剥夺/复氧后，雷帕霉素抑制了脑内皮细胞系bEnd.3中JMJD3的表达、紧密连接分子的丢失以及MMP-2/9的表达。因此，我们的结果表明，TRPM7在SCI后通过mTOR途径调节JMJD3表达，从而导致BSCB破坏。
