STAT3-mediated activation of miR-21 is involved in downregulation of TIMP3 and neovascularization in the ischemic retina
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Diana R. Gutsaeva1, Menaka Thounaojam1, Shubhra Rajpurohit1, Folami L. Powell2, Pamela M. Martin2, Stephanie Goei1, Michael Duncan3 and Manuela Bartoli1
1Department of Ophthalmology, Augusta University, Augusta, GA 30912, USA
2Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA
3Department of Internal Medicine, Section of Gastroenterology, Augusta University, Augusta, GA 30912, USA
Manuela Bartoli, email: [email protected]
Diana R. Gutsaeva, email: [email protected]
Keywords: ischemic retinopathies, retinal neovascularization, STAT3, miR-21, TIMP3
Received: August 01, 2017 Accepted: September 15, 2017 Published: October 06, 2017
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 pro-angiogenic effects in the ischemic retina, thus suggesting its blockade as a potential therapy to prevent/halt RNV.
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