STAT3-mediated activation of miR-21 is involved in downregulation of TIMP3 and neovascularization in the ischemic retina

Diana R. Gutsaeva, Menaka Thounaojam, Shubhra Rajpurohit, Folami L. Powell, Pamela M. Martin, Stephanie Goei, Michael Duncan, Manuela Bartoli

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Retinal neovascularization (RNV) is a sight threatening complication of ischemic retinopathies with limited therapeutic options. The transcription factor signal transducer and activator of transcription 3 (STAT3) has been shown to play a crucial role in promoting RNV. However, manipulating of STAT3 activity can cause significant adverse side effects due to its neurotrophic properties. In this study, we identified microRNA-21 (miR-21) as a downstream effector of STAT3 activity in the ischemic retinas and determined its role in promoting RNV through inhibition of its molecular target, the tissue inhibitor of matrix metalloproteinases 3 (TIMP3). Using human retinal endothelial cells (HREC) exposed to hypoxia and a mouse model of oxygen-induced retinopathy (OIR), we found that TIMP3 expression was significantly decreased at both mRNA and protein levels and this paralleled the activation of STAT3 and up-regulation of miR-21. Moreover, TIMP3 expression was restored by knockdown of STAT3 or blocking of miR-21 in HREC, thus, confirming TIMP3 as a downstream target of STAT3/miR-21 pathway. Finally, in a mouse model of OIR, blockade of miR-21 by a specific antisense (a.miR-21), halted RNV and this effect was associated with rescuing of TIMP3 expression. Our data show that miR-21 mediates STAT3 proangiogenic effects in the ischemic retina, thus suggesting its blockade as a potential therapy to prevent/halt RNV.

Original languageEnglish (US)
Pages (from-to)103568-103580
Number of pages13
JournalOncotarget
Volume8
Issue number61
DOIs
StatePublished - 2017

Keywords

  • Ischemic retinopathies
  • MiR-21
  • Retinal neovascularization
  • STAT3
  • TIMP3

ASJC Scopus subject areas

  • Oncology

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