MicroRNA-126-3p attenuates blood-brain barrier disruption, cerebral edema and neuronal injury following intracerebral hemorrhage by regulating PIK3R2 and Akt

Biochem Biophys Res Commun. 2017 Dec 9;494(1-2):144-151. doi: 10.1016/j.bbrc.2017.10.064. Epub 2017 Oct 14.

Abstract

MiR-126, a microRNA implicated in blood vessel integrity, angiogenesis and vascular inflammation, is markedly decreased in the sera of patients with intracerebral hemorrhage (ICH). The current study aims to evaluate the potential therapeutic effect of miR-126-3p on brain injuries in a rat model of collagenase-induced ICH. Intracerebroventricular administration of a miR-126-3p mimic significantly alleviated behavioral defects 24 h after ICH, as examined by paw placement and corner tests. ICH led to increased blood-brain barrier (BBB) permeability and cerebral edema, both of which were attenuated by miR-126-3p mimic. Treatment with miR-126-3p mimic reduced the numbers of myeloperoxidase (MPO)-positive, OX42-positive, Fluoro Jade B (FJB)-positive and NEUN/TUNEL double-positive cells around the hematoma, implying that miR-126-3p inhibited neutrophil infiltration, microglial activation and neuronal apoptosis following hemorrhage. In addition, miR-126-3p mimic suppressed the upregulation of phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2) in the perihematomal area and maintained the activation of Akt. Furthermore, in vitro assays confirmed upregulation of PIK3R2 upon knockdown of miR-126-3p in rat brain microvascular endothelial cells (BMECs), and silencing of miR-126-3p resulted in impaired BMEC barrier permeability and reversed vascular endothelial growth factor (VEGF)- and angiopoietin-1 (Ang-1)-induced activation of Akt and inhibition of BMEC apoptosis. In summary, our results suggest that exogenous miR-126-3p may alleviate BBB disruption, cerebral edema and neuronal injury following ICH by targeting PIK3R2 and the Akt signaling pathway in brain vascular endothelium.

Keywords: Akt; Intracerebral hemorrhage; PIK3R2; miR-126-3p.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiopoietin-1 / metabolism
  • Animals
  • Apoptosis / genetics
  • Blood-Brain Barrier / physiopathology*
  • Brain Edema / genetics*
  • Brain Edema / metabolism*
  • Brain Edema / therapy
  • Brain Injuries / genetics*
  • Brain Injuries / metabolism*
  • Brain Injuries / therapy
  • Cells, Cultured
  • Cerebral Hemorrhage / genetics*
  • Cerebral Hemorrhage / metabolism*
  • Cerebral Hemorrhage / therapy
  • Class Ia Phosphatidylinositol 3-Kinase / metabolism*
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Gene Knockdown Techniques
  • Male
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics*
  • MicroRNAs / therapeutic use
  • Molecular Mimicry
  • Neurons / metabolism
  • Neurons / pathology
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Angiopoietin-1
  • Angpt1 protein, rat
  • MIRN126 microRNA, rat
  • MicroRNAs
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, rat
  • PIK3R2 protein, rat
  • Class Ia Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt