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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amphetamine-Related Disorders / genetics
-
Amphetamine-Related Disorders / physiopathology*
-
Amphetamine-Related Disorders / therapy
-
Animals
-
Apoptosis Regulatory Proteins / antagonists & inhibitors
-
Apoptosis Regulatory Proteins / deficiency
-
Apoptosis Regulatory Proteins / genetics
-
Apoptosis Regulatory Proteins / metabolism
-
Blood-Brain Barrier / drug effects
-
Blood-Brain Barrier / physiology*
-
Cells, Cultured
-
Endothelial Cells / drug effects
-
Endothelial Cells / physiology
-
Gene Silencing
-
Humans
-
Male
-
Methamphetamine / adverse effects*
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
MicroRNAs / antagonists & inhibitors*
-
MicroRNAs / genetics
-
MicroRNAs / physiology
-
NF-kappa B / metabolism
-
Proto-Oncogene Proteins / antagonists & inhibitors
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins / metabolism
-
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
Substances
-
Apoptosis Regulatory Proteins
-
BBC3 protein, human
-
MIRN143 microRNA, human
-
MicroRNAs
-
MIRN143 microRNA, mouse
-
NF-kappa B
-
PUMA protein, mouse
-
Proto-Oncogene Proteins
-
TP53 protein, human
-
Tight Junction Proteins
-
Tumor Suppressor Protein p53
-
Tumor Suppressor Proteins
-
Methamphetamine