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Protein Kinase A Inhibitor H89 Attenuates Experimental Proliferative Vitreoretinopathy
Journal article   Open access   Peer reviewed

Protein Kinase A Inhibitor H89 Attenuates Experimental Proliferative Vitreoretinopathy

Yali Lyu, Wei Xu, Jieping Zhang, Mengwen Li, Qingyi Xiang, Yao Li, Tianhao Tan, Qingjian Ou, Jingfa Zhang, Haibin Tian, …
Investigative ophthalmology & visual science, v 61(2), pp 1-1
07 Feb 2020
DOI: https://doi.org/10.1167/iovs.61.2.1
PMID: 32031573
url
https://doi.org/10.1167/iovs.61.2.1View
Published, Version of Record (VoR)CC BY-NC-ND V4.0,  Open

Abstract

Aged Animals Cells, Cultured Cyclic AMP-Dependent Protein Kinase Catalytic Subunits - metabolism Electroretinography Epiretinal Membrane - metabolism Epithelial Cells - metabolism Female Humans Isoquinolines - antagonists & inhibitors Isoquinolines - pharmacology Male MAP Kinase Signaling System - physiology Middle Aged Retinal Pigment Epithelium - drug effects Smad Proteins - physiology Sulfonamides - antagonists & inhibitors Sulfonamides - pharmacology Transforming Growth Factor beta - antagonists & inhibitors Vitreoretinopathy, Proliferative - drug therapy
This study aimed to explore the role of the protein kinase A (PKA) pathway in proliferative vitreoretinopathy (PVR) and the effect of the PKA inhibitor H89 on experimental PVR. Epiretinal membranes (ERMs) were acquired from PVR patients and analyzed by frozen-section immunofluorescence. An in vivo model was developed by intravitreal injecting rat eyes with ARPE-19 cells and platelet-rich plasma, and changes in eye structures and vision function were observed. An in vitro epithelial-mesenchymal transition (EMT) cell model was established by stimulating ARPE-19 cells with transforming growth factor (TGF)-β. Alterations in EMT-related genes and cell function were detected. Mechanistically, PKA activation and activity were explored to assess the relationship between TGF-β1 stimulation and the PKA pathway. The effect of H89 on the TGF-β-Smad2/3 pathway was detected. RNA sequencing was used to analyze gene expression profile changes after H89 treatment. PKA was activated in human PVR membranes. In vivo, H89 treatment protected against structural changes in the retina and prevented decreases in electroretinogram b-wave amplitudes. In vitro, H89 treatment inhibited EMT-related gene alterations and partially reversed the functions of the cells. TGF-β-induced PKA activation was blocked by H89 pretreatment. H89 did not affect the phosphorylation or nuclear translocation of regulatory Smad2/3 but increased the expression of inhibitory Smad6. PKA pathway activation is involved in PVR pathogenesis, and the PKA inhibitor H89 can effectively inhibit PVR, both in vivo and in vitro. Furthermore, the protective effect of H89 is related to an increase in inhibitory Smad6.

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Web of Science research areas
Ophthalmology
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