Endoplasmic Reticulum Stress Response of Trabecular Meshwork Stem Cells and Trabecular Meshwork Cells and Protective Effects of Activated PERK Pathway

Wang, Yiwen; Osakue, Deborah; Yang, Eun‐Ju; Zhou, Yi; Gong, Haiyan; Xia, Xiaobo; Du, Yiqin

doi:10.1167/iovs.18-25477

Cited by 33 publications

(32 citation statements)

References 49 publications

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“…In support of this, we clearly demonstrate that treatment with ISRIB significantly reduces Dex-induced protein synthesis in TM cells, which is associated with a strong reduction in GADD34, ATF4, and CHOP levels while its effects on phosphorylation of eIF2α are minimal. A recent study by Wang et al (2019) independently demonstrated that the elF2α dephosphorylation inhibitor, Salubrinal prevents tunicamycin-induced TM cell death 87 . Moreover, dominant negative inhibitor of ATF4 reduced Dex-induced protein synthesis and ocular hypertension.…”

Section: Discussionmentioning

confidence: 99%

ATF4 leads to glaucoma by promoting protein synthesis and ER client protein load

et al. 2020

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The underlying pathological mechanisms of glaucomatous trabecular meshwork (TM) damage and elevation of intraocular pressure (IOP) are poorly understood. Here, we report that the chronic endoplasmic reticulum (ER) stress-induced ATF4-CHOP-GADD34 pathway is activated in TM of human and mouse glaucoma. Expression of ATF4 in TM promotes aberrant protein synthesis and ER client protein load, leading to TM dysfunction and cell death. These events lead to IOP elevation and glaucomatous neurodegeneration. ATF4 interacts with CHOP and this interaction is essential for IOP elevation. Notably, genetic depletion or pharmacological inhibition of ATF4-CHOP-GADD34 pathway prevents TM cell death and rescues mouse models of glaucoma by reducing protein synthesis and ER client protein load in TM cells. Importantly, glaucomatous TM cells exhibit significantly increased protein synthesis along with induction of ATF4-CHOP-GADD34 pathway. These studies indicate a pathological role of ATF4-CHOP-GADD34 pathway in glaucoma and provide a possible treatment for glaucoma by targeting this pathway.

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Section: Discussionmentioning

confidence: 99%

ATF4 leads to glaucoma by promoting protein synthesis and ER client protein load

et al. 2020

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“…All donor tissues were obtained and managed according to the guidelines in the Declaration of Helsinki for research involving human tissue and also approved by Ethics Committee of Xiangya Hospital, Central South University. Human TM cells were isolated and grown as described previously [9,10]. Briefly, the TM tissue was dissected and dissociated with 0.05% Trypsin for 20 min.…”

Section: Tm Cell Culturementioning

confidence: 99%

Cross-talk between MYOC p. Y437H mutation and TGF-β2 in the pathology of glaucoma

Yang

Abdulatef

Zhang³

et al. 2020

Int. J. Med. Sci.

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Objective: To identify the interaction between the MYOC Y437H mutation and TGF-β2 in a family with primary open-angle glaucoma (POAG). Methods: The MYOC Y437H mutation was identified in a family with POAG; the family was a fourth-generation family with 27 members, of which 6 members were affected. Analysis focused on the secreted myocilin protein and TGF-β2 found in the aqueous humor. Samples were taken both from normal controls and MYOC mutant carriers and cross-talk between MYOC Y437H and TGF-β2 were evaluated in the trabecular meshwork (TM) cells. Results: Aqueous humor secreted myocilin protein levels were reduced while TGF-β2 levels were increased in patients with the MYOC (c.1309T>C) mutation. This inverse relationship indicated that elevated TGF-β2 may be an important pathogenic mechanism in the progression of myocilin-related POAG. In TM cells expressing the MYOC Y437H mutant, exogenous TGF-β2 also significantly increased myocilin expression as well as the endoplasmic reticulum (ER) stress markers GRP94 and CHOP. This increase in TGF-β2 was also associated with increased cell death in cells carrying the MYOC Y437H mutation. Conclusion: These data collectively suggest that the mutual interaction between glaucomatous MYOC mutation and TGF-β2 contributed to the cell death of TM cells. This relationship also provides a new, therapeutic targets for the treatment of glaucoma.

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“…Importantly, our results suggest that care must be taken when considering cell-based therapeutic options (for example, stem cell or cell replacement options) 93 – 96 . This is because similar to resident pathologic cells 97 , a diseased ECM may inadvertently push newly transplanted cells towards a pathologic phenotype rather than ameliorate symptoms especially in the long term. However, inhibiting TGFβRI kinase reverses all these pathological outcomes irrespective of either stimuli or their interaction, suggesting it may potentially be used as an ocular hypotensive target.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid-induced cell-derived matrix modulates transforming growth factor β2 signaling in human trabecular meshwork cells

Yemanyi

Vranka

Raghunathan

2020

Sci Rep

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Aberrant remodeling of trabecular meshwork (TM) extracellular matrix (ECM) may induce ocular hypertensive phenotypes in human TM (hTM) cells to cause ocular hypertension, via a yet unknown mechanism. Here, we show that, in the absence of exogenous transforming growth factor-beta2 (TGFβ2), compared with control matrices (VehMs), glucocorticoid-induced cell-derived matrices (GIMs) trigger non-Smad TGFβ2 signaling in hTM cells, correlated with overexpression/activity of structural ECM genes (fibronectin, collagen IV, collagen VI, myocilin), matricellular genes (connective tissue growth factor [CTGF], secreted protein, acidic and rich in cysteine), crosslinking genes/enzymes (lysyl oxidase, lysyl oxidase-like 2–4, tissue transglutaminase-2), and ECM turnover genes/enzymes (matrix metalloproteinases-MMP2,14 and their inhibitors-TIMP2). However, in the presence of exogenous TGFβ2, VehMs and GIMs activate Smad and non-Smad TGFβ2 signaling in hTM cells, associated with overexpression of α-smooth muscle actin (α-SMA), and differential upregulation of aforementioned ECM genes/proteins with new ones emerging (collagen-I, thrombospondin-I, plasminogen activator inhibitor, MMP1, 9, ADAMTS4, TIMP1); with GIM-TGFβ2-induced changes being mostly more pronounced. This suggests dual glaucomatous insults potentiate profibrotic signaling/phenotypes. Lastly, we demonstrate type I TGFβ receptor kinase inhibition abrogates VehM-/GIM- and/or TGFβ2-induced upregulation of α-SMA and CTGF. Collectively, pathological TM microenvironments are sufficient to elicit adverse cellular responses that may be ameliorated by targeting TGFβ2 pathway.

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Endoplasmic Reticulum Stress Response of Trabecular Meshwork Stem Cells and Trabecular Meshwork Cells and Protective Effects of Activated PERK Pathway

Cited by 33 publications

References 49 publications

ATF4 leads to glaucoma by promoting protein synthesis and ER client protein load

ATF4 leads to glaucoma by promoting protein synthesis and ER client protein load

Cross-talk between MYOC p. Y437H mutation and TGF-β2 in the pathology of glaucoma

Glucocorticoid-induced cell-derived matrix modulates transforming growth factor β2 signaling in human trabecular meshwork cells

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