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

Abstract

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.

Inhibition of Methamphetamine Self-Administration and Reinstatement by Central Blockade of Angiotensin II Receptor in Rats

“…The current study demonstrated the downregulation of NAc miR-219p-5p targeting AT1R after METH SA, compared with yoked-METH and Saline rats. Current findings extend the increasing bodies of research that have demonstrated METHenabled alterations in a number of NAc miRNA expressions associated with various neuronal activities, including metabolism, apoptosis, autophagy, and immune response, potentially via the mitogen-activated protein kinase, CREB, G-protein-coupled receptor, and gonadotropin-releasing hormone signaling pathways (Zhu et al, 2015;Bai et al, 2016;Sim et al, 2017;Li et al, 2018;Zhang et al, 2018). A clinical study has also identified numerous miRNAs as negative regulators in patients with METH use disorder.…”

microRNAs Orchestrate Pathophysiology of Breast Cancer Brain Metastasis: Advances in Therapy

“…Angiogenic factors and growth factors either released by tumor cells or stromal cells individually or during their mutual crosstalk contribute to intravasation [89]. These factors allow tumor cells to invade through the basement membrane, adhere to the endothelial membrane, and pass through endothelial gap junctions to Table 1 miRNAs mediated regulation of BCBM miRNA Targets Regulation References EMT miR-8084 ING2, p53-BAX upregulated [16] miR-484 PAX-5 upregulated [19] miR-708-3p ZEB1, CDH2 and vimentin downregulated [17] miR-210 E-cadherin (ORF), PAX-5 upregulated [19] miR-142-3p Bach-1, CXCR4, MMP9, and VEGFR downregulated [18] miR-199a/214 Slug downregulated [51] miR-3178 Notch1 downregulated [52] miR-212-5p Prrx2 downregulated [53] miR-143 PUMA upregulated [35] miR-125a-5p ICAM-1 downregulated [38] miR-1258 HPSE downregulated [40] miR-210 Occludin, β-catenin upregulated [37] Cross Talk and Niche Formation miR-26a PTEN ATM upregulated [70,71] miR-19a PTEN upregulated [42] disseminate into the circulation [86]. Although no miRNA has been reported to influence intravasation directly, they can regulate angiogenic signals by targeting angiogenic factors and protein kinases.…”

“…PDPK1 degradation by miR-181c leads to the downregulation of phosphorylated cofilin and a resultant activated cofilin-induced modulation of actin dynamics [69]. MiR-143 enhances the permeability of endothelial cells through targeting p53 upregulated modulator of apoptosis (PUMA), and consequently shows a reduction of tight junction proteins (TJPs) [35]. Additionally, miR-125a-5p has been shown to be an important player in the maintenance of the integrity of the BBB.…”

“…d miR-210 directly targets β-Catenin and Occudin to disrupt the integrity of the BBB [37]. e MiR-143 decreases the expression of TJs by directly targeting p53 upregulated modulator of apoptosis (PUMA) and increases the permeability of human brain endothelial cells [35] homeostasis and immunosurveillance [128][129][130]. Microglia release cytokines and interleukins that support cancer invasion and colonization of the parenchyma.…”

“…Growing evidence has demonstrated the role of miRNA in different steps of the metastatic process, including in BCBM, such as the epithelial to mesenchymal transition (EMT) [16][17][18][19], local invasion [20][21][22][23], intravasation [24][25][26][27][28][29][30], survival in circulation [31][32][33], extravasation [34], the integrity of the BBB [35][36][37][38][39][40], niche formation [41,42], and colonization in the brain parenchyma [43][44][45]. MiRNAs are 20-22 short nucleotide sequences that often negatively regulate gene expression through the imperfect binding of their seed sequences to the 3'UTR region of target genes [46].…”