Silencing microRNA-143 protects the integrity of the blood-brain barrier: implications for methamphetamine abuse

• Published in: Scientific reports 2016-10, Vol.6 (1), p.35642, Article 35642
• Main Authors: Bai, Ying, Zhang, Yuan, Hua, Jun, Yang, Xiangyu, Zhang, Xiaotian, Duan, Ming, Zhu, Xinjian, Huang, Wenhui, Chao, Jie, Zhou, Rongbin, Hu, Gang, Yao, Honghong
• Format: Article
• Language: English
• Subjects: 13/109; 14/32; 38/89; 631/337/384/331; 631/378/1341; Amphetamine-Related Disorders - genetics; Amphetamine-Related Disorders - physiopathology; Amphetamine-Related Disorders - therapy; Animal models; Animals; Apoptosis Regulatory Proteins - antagonists & inhibitors; Apoptosis Regulatory Proteins - deficiency; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - physiology; Cells, Cultured; Drug abuse; Endothelial Cells - drug effects; Endothelial Cells - physiology; Gene Silencing; Humanities and Social Sciences; Humans; Kinases; Male; Methamphetamine; Methamphetamine - adverse effects; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; MicroRNAs - antagonists & inhibitors; MicroRNAs - genetics; MicroRNAs - physiology; multidisciplinary; NF-kappa B - metabolism; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Science; Signal transduction; Signal Transduction - drug effects; Tight Junction Proteins - metabolism; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - deficiency; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep35642

MicroRNA-143 (miR-143) plays a critical role in various cellular processes; however, the role of miR-143 in the maintenance of blood-brain barrier (BBB) integrity remains poorly defined. Silencing miR-143 in a genetic animal model or via an anti-miR-143 lentivirus prevented the BBB damage induced by methamphetamine. miR-143, which targets p53 unregulated modulator of apoptosis (PUMA), increased the permeability of human brain endothelial cells and concomitantly decreased the expression of tight junction proteins (TJPs). Silencing miR-143 increased the expression of TJPs and protected the BBB integrity against the effects of methamphetamine treatment. PUMA overexpression increased the TJP expression through a mechanism that involved the NF-κB and p53 transcription factor pathways. Mechanistically, methamphetamine mediated up-regulation of miR-143 via sigma-1 receptor with sequential activation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3′ kinase (PI3K)/Akt and STAT3 pathways. These results indicated that silencing miR-143 could provide a novel therapeutic strategy for BBB damage-related vascular dysfunction.