Abstract
Purpose :
Signal transducer and activator of transcription 3 (STAT3) plays an important role in inflammation and angiogenesis. Previous studies have shown that STAT3 is involved in retinal damage in pre-clinical models of type-1 diabetes and that ocular fluid from proliferative diabetic retinopathy (PDR) patients contains high levels of IL-6, a key activator of the STAT3 pathway. We hypothesize that inhibition of STAT3 may ameliorate pathologic neo-vascular growth in PDR.
Methods :
The effect of STAT3 inhibition on pathologic retinal neovascularization was tested on a preclinical model of PDR, the mouse model of oxygen-induced retinopathy (OIR). New-born C57BL6/J mouse pups (n ≥ 5 per group) were exposed to 75% O2 from post-natal day 7 (P7) to P12. Mice were then treated from P13 to P16 by daily intraperitoneal injection of a STAT3 inhibitor (LLL12, 5mg/kg) or vehicle (1% DMSO in PBS). The expression of phosphorylated STAT3 (pSTAT3) in the retinas was examined by Western blotting at different time-points (P12 to P22). At P17 eyes were collected and the extent of retinal neo-vascularization/vaso-obliteration examined in retinal flat-mounts by dual staining of isolectin-B4 and collagen IV. Retinal thickness was assessed in haematoxylin and eosin stained cross-sections. Retinal function was assessed by electroretinography (ERG) and retinal thickness by SD-OCT at P90. Data were analyzed by two-way ANOVA followed by Bonferroni’s post-test.
Results :
The expression of pSTAT3 was significantly increased in OIR eyes from P16 to P22. LLL12 treatment significantly decreased neo-vascular tufts area in OIR mice (6% ± 1.2%; p<0.001) compared to vehicle treated (12% ± 0.5%) and non-injected controls (15.5% ± 1.5%) at P17. This was accompanied by a significant preservation of retinal thickness in LLL12-treated mice (90.1 ± 2.3 μm; vehicle 74.5 ± 2 μm; non-injected 76.7 ± 3.1 μm; p<0.01). The extent of retinal vaso-obliteration was not significantly affected by the treatment. LLL12 treatment significantly improved retinal function (scotopic a-wave and b-wave amplitudes, p<0.001) and retinal thickness (p<0.05) by P90.
Conclusions :
Our results suggest that STAT3 activation may contribute to pathologic neo-vascular growth in the murine model of OIR. STAT3 may be a therapeutic target for retinal neovascular disorders such as PDR.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.