Zika virus NS1 suppresses VE-cadherin via hsa-miR-29b-3p/DNMT3b/MMP-9 pathway in human brain microvascular endothelial cells

Cell Signal. 2023 Jun:106:110659. doi: 10.1016/j.cellsig.2023.110659. Epub 2023 Mar 21.

Abstract

Zika virus infection has been reported to cause microcephaly in newborns. ZIKV exploits various strategies to cross the blood-brain barrier. ZIKV NS1 may compromise the barrier integrity of endothelial cells by regulating expression of junctional proteins. MicroRNAs play an important role in post-transcriptional gene regulations. We demonstrated that ZIKV-NS1 affected the adherence junction protein in human brain microvascular endothelial cells via hsa-miR-29b-3p/DNMT3b/MMP-9 pathway. The hCMEC/D3 cells were exposed to ZIKV-NS1 with different doses (500 ng/mL and 1000 ng/mL) for 24 h. The expression pattern of DNTM3b, MMP-9, and VE-cadherin were studied using immunoblotting and the distribution of DNMT3b and MMP-9 were studied using immunofluorescence. The quantification of hsa-miR-29b-3p was done through qRT-PCR. Direct regulation of DNMT3b by hsa-miR-29b-3p was demonstrated by overexpression of hsa-miR-29b-3p using hsa-miR-29b-3p mimic, and knockdown of hsa-miR-29b-3p by using hsa-miR-29b-3p inhibitors. The ZIKV-NS1 affected the barrier function of endothelial cells through the increased expression of hsa-miR29b-3p, which suppressed the DNMT3b, thus enhanced expression of MMP-9, which finally suppressed the expression of VE-cadherin. These findings suggested that ZIKV-NS1 alters the expression of Adherens Junction protein in human brain microvascular endothelial cells through hsa-miR-29b-3p/DNMT3b/MMP-9 pathway, which compromised the barrier function of human brain microvascular endothelial cells.

Keywords: Blood-brain-barrier; Endothelial-barrier permeability; Junctional proteins; MicroRNA; Non-structural protein 1 (NS1); Zika virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / metabolism
  • Endothelial Cells / metabolism
  • Humans
  • Infant, Newborn
  • Matrix Metalloproteinase 9 / metabolism
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Zika Virus Infection* / metabolism
  • Zika Virus* / genetics
  • Zika Virus* / metabolism

Substances

  • MIRN29B1 microRNA, human
  • cadherin 5
  • Matrix Metalloproteinase 9
  • MicroRNAs