Rho GTPase signaling promotes constitutive expression and release of TGF-ß2 by human trabecular meshwork cells.
Exp Eye Res
; 146: 95-102, 2016 05.
Article
em En
| MEDLINE
| ID: mdl-26743044
ABSTRACT
Elevated intraocular pressure (IOP) is causally implicated in the pathophysiology of primary open-angle glaucoma (POAG). The molecular mechanisms responsible for elevated IOP remain elusive, but may involve aberrant expression and signaling of transforming growth factor (TGF)-ß2 within the trabecular meshwork (TM). Consistent with previously published studies, we show here that exogenous addition of TGF-ß2 to cultured porcine anterior segments significantly attenuates outflow facility in a time-dependent manner. By comparison, perfusing segments with a TGFßRI/ALK-5 antagonist (SB-431542) unexpectedly elicited a significant and sustained increase in outflow facility, implicating a role for TM-localized constitutive expression and release of TGF-ß2. Consistent with this thesis, cultured primary or transformed (GTM3) quiescent human TM cells were found to constitutively express and secrete measurable amounts of biologically-active TGF-ß2. Disrupting monomeric GTPase post-translational prenylation and activation with lovastatin or GGTI-298 markedly reduced constitutive TGF-ß2 expression and release. Specifically, inhibiting the Rho subfamily of GTPases with C3 exoenzyme similarly reduced constitutive expression and secretion of TGF-ß2. These findings suggest that Rho GTPase signaling, in part, regulates constitutive expression and release of biologically-active TGF-ß2 from human TM cells. Localized constitutive expression and release of TGF-ß2 by TM cells may promote or exacerbate elevation of IOP in POAG.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Malha Trabecular
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RNA
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Regulação da Expressão Gênica
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Glaucoma de Ângulo Aberto
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Proteínas rho de Ligação ao GTP
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Fator de Crescimento Transformador beta2
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Pressão Intraocular
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Exp Eye Res
Ano de publicação:
2016
Tipo de documento:
Article