AR12286 Alleviates TGF-β-Related Myofibroblast Transdifferentiation and Reduces Fibrosis after Glaucoma Filtration Surgery

Abstract

Scar formation can cause the failure of glaucoma filtration surgery. We investigated the effect of AR12286, a selective Rho-associated kinase inhibitor, on myofibroblast transdifferentiation and intraocular pressure assessment in rabbit glaucoma filtration surgery models. Cell migration and collagen contraction were used to demonstrate the functionality of AR12286-modulated human conjunctival fibroblasts (HConFs). Polymerase chain reaction quantitative analysis was used to determine the effect of AR12286 on the production of collagen Type 1A1 and fibronectin 1. Cell migration and collagen contraction in HConFs were activated by TGF-β1. However, compared with the control group, rabbit models treated with AR12286 exhibited higher reduction in intraocular pressure after filtration surgery, and decreased collagen levels at the wound site in vivo. Therefore, increased α-SMA expression in HConFs induced by TGF-β1 could be inhibited by AR12286, and the production of Type 1A1 collagen and fibronectin 1 in TGF-β1-treated HConFs was inhibited by AR12286. Overall, the stimulation of HConFs by TGF-β1 was alleviated by AR12286, and this effect was mediated by the downregulation of TGF-β receptor-related SMAD signaling pathways. In vivo results indicated that AR12286 thus improves the outcome of filtration surgery as a result of its antifibrotic action in the bleb tissue because AR12286 inhibited the TGF-β receptor-related signaling pathway, suppressing several downstream reactions in myofibroblast transdifferentiation.

Knockdown of lncRNA PVT1 protects human trabecular meshwork cells against H2O2-induced injury via the regulation of the miR-29a-3p/VEGF/MMP-2 axis

“…Targeting VEGFA and MMP-2 by modulating the levels of lncRNA PVT1 and miR-29a-3p could effectively ameliorate cellular apoptosis, migratory ability, and viability of HTMCs under oxidative stress. It has been documented that antifibrotic therapy in the bleb tissue in vivo targeted at inhibiting α-SMA expression significantly suppressed myofibroblast transdifferentiation and reduced IOP after filtration surgery in a rabbit model of glaucoma filtration surgery [ 47 ]. The findings of this work supported that targeting the lncRNA PVT1/miR-29a-3p/VEGFA/MMP-2 axis has potential as a strategy for ameliorating fibrosis and scar formation in filtration blebs after trabeculectomy.…”

TGF-β Isoforms Affect the Planar and Subepithelial Fibrogenesis of Human Conjunctival Fibroblasts in Different Manners

“…However, in contrast to several investigations that focused on the effects of TGF-β-1 and TGF-β-2 on the pathogenesis of glaucoma using HTM cells [32,61,62] and conjunctival fibrosis [37,38,46,47,[63][64][65], the influence of TGF-β-3 has not been extensively investigated so far. Therefore, additional studies will be required to elucidate the physiological and pathological significance of these three TGF-β isoforms, especially focusing on TGF-β-3 toward conjunctiva in more detail using RNA sequencing analysis, SiRNA inhibition of the specific target molecules of their downstream signaling, and others as our next project.…”

Rho-Kinase Inhibitors – A New Broad-Spectrum Treatment in Ophthalmic Diseases. A Review

“…Currently, rho-kinase inhibitors are administered following filtering surgical treatment for glaucoma. Post-trabeculectomy ROCK inhibitors have been shown to have a beneficial effect due to their properties of inhibiting fibroblast proliferation, migration and cell adhesion, thus promoting wound healing and preventing scar formation in the filtering bleb [12,35]. The first rho-kinase medication approved to treat glaucoma was Ripasudil hydrochloride hydrate 0.4%.…”