Zhang Yanhong, Zhang Yuan, Bai Ying, Chao Jie, Hu Gang, Chen Xufeng, Yao Honghong
Department of Pharmacology, Medical School of Southeast University, Nanjing, China.
Department of Physiology, Medical School of Southeast University, Nanjing, China.
Exp Cell Res. 2017 Jul 1;356(1):28-39. doi: 10.1016/j.yexcr.2017.04.007. Epub 2017 Apr 10.
Mounting evidence indicates that methamphetamine causes blood-brain barrier damage, with emphasis on endothelial cells. The role of pericytes in methamphetamine-induced BBB damage remains unknown. Our study demonstrated that methamphetamine increased the migration of pericytes from the endothelial basement membrane. However, the detailed mechanisms underlying this process remain poorly understood. Thus, we examined the molecular mechanisms involved in methamphetamine-induced pericyte migration. The results showed that exposure of C3H/10T1/2 cells and HBVPs to methamphetamine increased PUMA expression via activation of the sigma-1 receptor, MAPK and Akt/PI3K pathways. Moreover, methamphetamine treatment resulted in the increased migration of C3H/10T1/2 cells and HBVPs. Knockdown of PUMA in pericytes transduced with PUMA siRNA attenuated the methamphetamine-induced increase in cell migration through attenuation of integrin and tyrosine kinase mechanisms, implicating a role of PUMA in the migration of C3H/10T1/2 cells and HBVPs. This study has demonstrated that methamphetamine-mediated pericytes migration involves PUMA up-regulation. Thus, targeted studies of PUMA could provide insights to facilitate the development of a potential therapeutic approach for alleviation of methamphetamine-induced pericyte migration.
越来越多的证据表明，甲基苯丙胺会导致血脑屏障损伤，尤其是对内皮细胞的损伤。周细胞在甲基苯丙胺诱导的血脑屏障损伤中的作用尚不清楚。我们的研究表明，甲基苯丙胺会增加周细胞从内皮基底膜的迁移。然而，这一过程背后的详细机制仍知之甚少。因此，我们研究了甲基苯丙胺诱导周细胞迁移所涉及的分子机制。结果显示，将C3H/10T1/2细胞和人脑微血管周细胞（HBVPs）暴露于甲基苯丙胺会通过激活σ-1受体、丝裂原活化蛋白激酶（MAPK）和Akt/磷脂酰肌醇-3-激酶（PI3K）途径增加p53上调凋亡调节因子（PUMA）的表达。此外，甲基苯丙胺处理导致C3H/10T1/2细胞和HBVPs的迁移增加。用PUMA小干扰RNA（siRNA）转导的周细胞中PUMA的敲低通过整合素和酪氨酸激酶机制的减弱减弱了甲基苯丙胺诱导的细胞迁移增加，这表明PUMA在C3H/10T1/2细胞和HBVPs的迁移中起作用。这项研究表明，甲基苯丙胺介导的周细胞迁移涉及PUMA的上调。因此，对PUMA的靶向研究可为开发减轻甲基苯丙胺诱导的周细胞迁移的潜在治疗方法提供见解。
