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

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5 Citations (Scopus)

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 - Jan 1 2017

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Tissue Inhibitor of Metalloproteinase-3
STAT3 Transcription Factor
Matrix Metalloproteinase 3
Retinal Neovascularization
MicroRNAs
Retina
Down-Regulation
Endothelial Cells
Oxygen
Transcription Factors
Up-Regulation
Messenger RNA
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

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title = "STAT3-mediated activation of miR-21 is involved in downregulation of TIMP3 and neovascularization in the ischemic retina",
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.",
keywords = "Ischemic retinopathies, MiR-21, Retinal neovascularization, STAT3, TIMP3",
author = "Gutsaeva, {Diana R.} and Menaka Thounaojam and Shubhra Rajpurohit and Powell, {Folami L.} and Martin, {Pamela M.} and Stephanie Goei and Michael Duncan and Manuela Bartoli",
year = "2017",
month = "1",
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language = "English (US)",
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T1 - STAT3-mediated activation of miR-21 is involved in downregulation of TIMP3 and neovascularization in the ischemic retina

AU - Gutsaeva, Diana R.

AU - Thounaojam, Menaka

AU - Rajpurohit, Shubhra

AU - Powell, Folami L.

AU - Martin, Pamela M.

AU - Goei, Stephanie

AU - Duncan, Michael

AU - Bartoli, Manuela

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

KW - Ischemic retinopathies

KW - MiR-21

KW - Retinal neovascularization

KW - STAT3

KW - TIMP3

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