scholarly journals Aspirin inhibits TGFβ2-induced epithelial to mesenchymal transition of lens epithelial cells: selective acetylation of K56 and K122 in histone H3

2020 ◽  
Vol 477 (1) ◽  
pp. 75-97 ◽  
Author(s):  
Mi-Hyun Nam ◽  
Andrew J.O. Smith ◽  
Mina B. Pantcheva ◽  
Ko Uoon Park ◽  
Joseph A. Brzezinski ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Histone H3 ◽  
Posterior Capsule ◽  
Human Lens ◽  
Lens Epithelial Cells ◽  
Promoter Regions ◽  
Mesenchymal Transition

Posterior capsule opacification (PCO) is a complication after cataract surgery that can disrupt vision. The epithelial to mesenchymal transition (EMT) of lens epithelial cells (LECs) in response to transforming growth factor β2 (TGFβ2) has been considered an obligatory mechanism for PCO. In this study, we tested the efficacy of aspirin in inhibiting the TGFβ2-mediated EMT of human LECs, LECs in human lens capsular bags, and lensectomized mice. In human LECs, the levels of the EMT markers α-smooth muscle actin (α-SMA) and fibronectin were drastically reduced by treatment with 2 mM aspirin. Aspirin also halted the EMT response of TGFβ2 when introduced after EMT initiation. In human capsular bags, treatment with 2 mM aspirin significantly suppressed posterior capsule wrinkling and the expression α-SMA in capsule-adherent LECs. The inhibition of TGFβ2-mediated EMT in human LECs was not dependent on Smad phosphorylation or MAPK and AKT-mediated signaling. We found that aspirin significantly increased the acetylation of K56 and K122 in histone H3 of human LECs. Chromatin immunoprecipitation assays using acetyl-H3K56 or acetyl-H3K122 antibody revealed that aspirin blocked the TGFβ2-induced acetylation of H3K56 and H3K122 at the promoter regions of ACTA2 and COL1A1. After lensectomy in mice, we observed an increase in the proliferation and α-SMA expression of the capsule-adherent LECs, which was ameliorated by aspirin administration through drinking water. Taken together, our results showed that aspirin inhibits TGFβ2-mediated EMT of LECs, possibly from epigenetic down-regulation of EMT-related genes.

Transforming growth factor-β2-mediated mesenchymal transition in lens epithelial cells is repressed in the absence of RAGE

2021 ◽  
Vol 478 (12) ◽  
pp. 2285-2296
Author(s):  
Mi-Hyun Nam ◽  
Mina B. Pantcheva ◽  
Johanna Rankenberg ◽  
Ram H. Nagaraj
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Knockout Mice ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Lens Epithelial Cells ◽  
Wild Type ◽  
Mesenchymal Transition ◽  
Smad Signaling ◽  
Transforming Growth Factor Β2

Transforming growth factor-β2 (TGFβ2)-mediated epithelial to mesenchymal transition (EMT) in lens epithelial cells (LECs) has been implicated in fibrosis associated with secondary cataracts. In this study, we investigated whether the receptor for advanced glycation end products (RAGE) plays a role in TGFβ2-mediated EMT in LECs. Unlike in the LECs from wild-type mice, TGFβ2 failed to elicit an EMT response in LECs from RAGE knockout mice. The lack of RAGE also diminished TGFβ2-mediated Smad signaling. In addition, treatment with TGFβ2 increased IL-6 levels in LECs from wild-type mice but not in those from RAGE knockout mice. Treatment of human LECs with the RAGE inhibitor FPS-ZM1 reduced TGFβ2-mediated Smad signaling and the EMT response. Unlike that in wild-type lenses, the removal of fiber cell tissue in RAGE knockout lenses did not result in elevated levels of α-smooth muscle actin (α-SMA), fibronectin (FN), and integrin β1 in capsule-adherent LECs. Taken together, these results suggest that TGFβ2 signaling is intricately linked to RAGE. Targeting RAGE could be explored as a therapeutic strategy against secondary cataracts.

scholarly journals Matrix-bound AGEs enhance TGFβ2-mediated mesenchymal transition of lens epithelial cells via the noncanonical pathway: implications for secondary cataract formation

2018 ◽  
Vol 475 (8) ◽  
pp. 1427-1440 ◽  
Author(s):  
Mi-Hyun Nam ◽  
Ram H. Nagaraj
Keyword(s):  
Epithelial Cells ◽  
P38 Mapk ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Lens Epithelial Cells ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Noncanonical Pathway ◽  
Αb Crystallin

Advanced glycation end products (AGEs) are post-translational modifications formed from the reaction of reactive carbonyl compounds with amino groups in proteins. Our laboratory has previously shown that AGEs in extracellular matrix (ECM) proteins promote TGFβ2 (transforming growth factor-beta 2)-mediated epithelial-to-mesenchymal transition (EMT) of lens epithelial cells (LECs), which could play a role in fibrosis associated with posterior capsule opacification. We have also shown that αB-crystallin plays an important role in TGFβ2-mediated EMT of LECs. Here, we investigated the signaling mechanisms by which ECM-AGEs enhance TGFβ2-mediated EMT in LECs. We found that in LECs cultured on AGE-modified basement protein extract (AGE-BME), TGFβ2 treatment up-regulated the mesenchymal markers α-SMA (α-smooth muscle actin) and αB-crystallin and down-regulated the epithelial marker E-cadherin more than LECs cultured on unmodified BME and treated with TGFβ2. Using a Multiplex Assay, we found that AGE-BME significantly up-regulated the noncanonical pathway by promoting phosphorylation of ERK (extracellular signal-regulated kinases), AKT, and p38 MAPK (mitogen-activated protein kinases) during TGFβ2-mediated EMT. This EMT response was strongly suppressed by inhibition of AKT and p38 MAPK phosphorylation. The AKT inhibitor LY294002 also suppressed TGFβ2-induced up-regulation of nuclear Snail and reduced phosphorylation of GSK3β. Inhibition of Snail expression suppressed TGFβ2-mediated α-SMA expression. αB-Crystallin was up-regulated in an AKT-dependent manner during AGE-BME/TGFβ2-mediated EMT in LECs. The absence of αB-crystallin in LECs suppressed TGFβ2-induced GSK3β phosphorylation, resulting in lower Snail levels. Taken together, these results show that ECM-AGEs enhance the TGFβ2-mediated EMT response through activation of the AKT/Snail pathway, in which αB-crystallin plays an important role as a linker between the TGFβ2 and AGE-mediated signaling pathways.

scholarly journals RNA Interference TargetingSnailInhibits the Transforming Growth Factorβ2-Induced Epithelial-Mesenchymal Transition in Human Lens Epithelial Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Ping Li ◽  
Jiaona Jing ◽  
Jianyan Hu ◽  
Tiejun Li ◽  
Yuncheng Sun ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Human Lens ◽  
Lens Epithelial Cells ◽  
Epithelial Cell Line ◽  
Migration Ability ◽  
Mesenchymal Transition ◽  
Response Characteristics ◽  
Human Lens Epithelial Cells

Epithelial-msenchymal transition (EMT) contributes to posterior capsule opacification (PCO) type of cataract. Transcription factorsSnailis a key trigger of EMT activated by transforming growth factorβ(TGFβ). This study was done to investigate the effect ofSnailtargeting siRNA on TGFβ2-induced EMT in human lens epithelial cells. TGFβ2 treatment of cultured human epithelial cell line (HLEB3) upregulated the expression ofSnailand the EMT relevant molecules such as vimentin andα-SMA but downregulated the expression of keratin and E-cadherin. After the stimulation of TGFβ2, the HLEB3 cells became fibroblast-like in morphology, and the junctions of cell-cell disappeared. TGFβ2 treatment also enhanced migration ability of HLEB3 cells. TGFβ2-inducedSnailexpression and EMT were significantly inhibited bySnailsiRNA. By analyzing the response characteristics of HLEB3 in TGFβ2-induced EMT model with/withoutSnail-specific siRNA, we concluded thatSnailis an element in the EMT of HLEB3 cells induced by TGFβ2.SnailsiRNA targeting can block the induced EMT and therefore has the potential to suppress the development of PCO.

scholarly journals αB-crystallin is essential for the TGF-β2-mediated epithelial to mesenchymal transition of lens epithelial cells

2016 ◽  
Vol 473 (10) ◽  
pp. 1455-1469 ◽  
Author(s):  
Rooban B. Nahomi ◽  
Mina B. Pantcheva ◽  
Ram H. Nagaraj
Keyword(s):  
Growth Factor ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Therapeutic Target ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Lens Epithelial Cell ◽  
Lens Epithelial Cells ◽  
Mesenchymal Transition ◽  
Αb Crystallin

We found that αB-crystallin promoted transforming growth factor (TGF)-β2-induced epithelial to mesenchymal transition (EMT) in lens epithelial cell (LEC) and its depletion resulted in reduced EMT in cultured LEC and in lensectomized mice. αB-Crystallin could be a therapeutic target to block secondary cataract.

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