RhoA/ROCK Signaling Regulates TGF-β1-Induced Fibrotic Effects in Human Pterygium Fibroblasts through MRTF-A

Jul 29, 2021Current eye research

RhoA/ROCK signaling controls scarring caused by TGF-β1 in human pterygium fibroblast cells through MRTF-A

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Abstract

ROCK inhibitor Y-27632 reduced TGF-β1-induced cell proliferation and migration in human pterygium fibroblasts.

TGF-β1 is associated with increased expression of profibrotic markers in primary human pterygium fibroblasts.
Inhibition of RhoA/ROCK signaling decreased the TGF-β1-induced expression of alpha-smooth muscle actin, collagen types I and III, and matrix metalloproteinase-9.
The ROCK inhibitor Y-27632 suppressed nuclear accumulation of Myocardin-related transcription factor A in response to TGF-β1.
MRTF-A/SRF transcription pathway inhibition reduced TGF-β1-induced activation of myofibroblasts.
RhoA/ROCK signaling may play a crucial role in TGF-β1-induced fibrosis and myofibroblast activation.

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PURPOSE: The overexpression of transforming growth factor-beta1 (TGF-β1) after surgical excision often leads to excessive fibrosis, indicating the recurrence of pterygium. The aims of the present in vitro study were to investigate the role of RhoA/ROCK signaling in regulating fibrotic effects of primary human pterygium fibroblasts (HPFs), as well as to explore the possible mechanisms of these effects.

METHODS: Pterygium samples were obtained from surgery, and profibrotic activation was induced by TGF-β1. Cell proliferation was detected by CCK-8 assay; cell migration was detected by wound healing assay; quantitative real-time PCR and Western blot were used to detect the effects of TGF-β1 and the role of RhoA/ROCK signaling in the synthesis of alpha-smooth muscle actin (a-SMA), type I and III collagen (COL1 and COL3), and matrix metalloproteinase-9 (MMP9) in HPFs. The changes of signaling pathways were detected by Western blot; and pharmaceutical inhibition of RhoA/ROCK signaling and its downstream MRFT-A/SRF transcription pathway were used to assess their possible mechanism in HPFs fibrosis.

RESULTS: ROCK inhibitor Y-27632 decreased TGF-β1-induced cell proliferation and migration, reduced the TGF-β1-induced expression of profibrotic markers in HPFs, and suppressed TGF-β1-induced nuclear accumulation of Myocardin-related transcription factor A (MRTF-A) as well as accompanied elevation of F/G-actin ratio in HPFs. MRTF-A/Serum response factor (SRF) inhibitor CCG-100602 attenuated the TGF-β1-induced α-SMA expression and reduced myofibroblast activation in HPFs.

CONCLUSIONS: RhoA/ROCK signaling played a pivotal role in TGF-β1-induced fibrosis and myofibroblast activation in HPFs at least in part by inactivating the downstream MRTF-A/SRF transcriptional pathway.

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RhoA/ROCK Signaling Regulates TGF-β1-Induced Fibrotic Effects in Human Pterygium Fibroblasts through MRTF-A

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