Abstract
Studies from our laboratory have suggested that activation of αvβ3 integrin-mediated signaling could contribute to the fibrotic-like changes observed in primary open angle glaucoma (POAG) and glucocorticoid-induced glaucoma. To determine how αvβ3 integrin signaling could be involved in this process, RNA-Seq analysis was used to analyze the transcriptomes of immortalized trabecular meshwork (TM) cell lines overexpressing either a control vector or a wild type (WT) or a constitutively active (CA) αvβ3 integrin. Compared to control cells, hierarchical clustering, PANTHER pathway and protein-protein interaction (PPI) analysis of cells overexpressing WT-αvβ3 integrin or CA-αvβ3 integrin resulted in a significant differential expression of genes encoding for transcription factors, adhesion and cytoskeleton proteins, extracellular matrix (ECM) proteins, cytokines and GTPases. Cells overexpressing a CA-αvβ3 integrin also demonstrated an enrichment for genes encoding proteins found in TGFβ2, Wnt and cadherin signaling pathways all of which have been implicated in POAG pathogenesis. These changes were not observed in cells overexpressing WT-αvβ3 integrin. Our results suggest that activation of αvβ3 integrin signaling in TM cells could have significant impacts on TM function and POAG pathogenesis.
Highlights
Glaucoma is a chronic optic neuropathy that results in irreversible blindness [1]. the exact etiology of glaucoma remains unknown, a number of studies have determined that elevated levels of transforming growth factor β2 (TGFβ2) and connective tissue growth factor (CTGF) and the use of glucocorticoids can lead to the development of glaucoma [2,3]
The exact etiology of glaucoma remains unknown, a number of studies have determined that elevated levels of transforming growth factor β2 (TGFβ2) and connective tissue growth factor (CTGF) and the use of glucocorticoids can lead to the development of glaucoma [2,3]
All cause an increase in extracellular matrix (ECM) deposition and cytoskeleton changes associated with contractility that lead to a restriction in aqueous humor outflow and together contribute to the elevation of intraocular pressure (IOP)
Summary
Glaucoma is a chronic optic neuropathy that results in irreversible blindness [1]. the exact etiology of glaucoma remains unknown, a number of studies have determined that elevated levels of transforming growth factor β2 (TGFβ2) and connective tissue growth factor (CTGF) and the use of glucocorticoids can lead to the development of glaucoma [2,3]. Recent studies have shown that the activation of αvβ integrin signaling plays a role in regulating these changes in ECM deposition and contractility. The activity of the αvβ integrin in human trabecular meshwork (HTM) cells can be increased by the glucocorticoid dexamethasone via the calcineurin/NFATc1 pathway [12] This pathway has been associated with glaucoma since it regulates the expression of myocilin, a protein involved in an early onset form of POAG and GC-induced ocular hypertension [13]. Together these results suggest that αvβ integrin signaling can contribute to the development of glaucoma. The differential expression of genes between these cell lines was analyzed using various bioannotations, network and pathway analysis databases to determine specific signaling pathways and categories of genes that may be altered when αvβ integrin is active
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