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Abstract #66270 Published in IGR 17-3
Rho GTPase signaling promotes constitutive expression and release of TGF-β2 by human trabecular meshwork cells
Pervan CL; Lautz JD; Blitzer AL; Langert KA; Stubbs EBExperimental Eye Research 2015; 146: 95-102
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)-β2 within the trabecular meshwork (TM). Consistent with previously published studies, we show here that exogenous addition of TGF-β2 to cultured porcine anterior segments significantly attenuates outflow facility in a time-dependent manner. By comparison, perfusing segments with a TGFβRI/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-β2. 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-β2. Disrupting monomeric GTPase post-translational prenylation and activation with lovastatin or GGTI-298 markedly reduced constitutive TGF-β2 expression and release. Specifically, inhibiting the Rho subfamily of GTPases with C3 exoenzyme similarly reduced constitutive expression and secretion of TGF-β2. These findings suggest that Rho GTPase signaling, in part, regulates constitutive expression and release of biologically-active TGF-β2 from human TM cells. Localized constitutive expression and release of TGF-β2 by TM cells may promote or exacerbate elevation of IOP in POAG.
Research Service, Department of Veterans Affairs, Edward Hines Jr. VA Hospital, Hines, IL, USA; Department of Ophthalmology, Loyola University Chicago, Maywood, IL, USA. Electronic address: cynthia.pervan@va.gov.
Full articleClassification:
3.6 Cellular biology (Part of: 3 Laboratory methods)
3.8 Pharmacology (Part of: 3 Laboratory methods)
2.5.1 Trabecular meshwork (Part of: 2 Anatomical structures in glaucoma > 2.5 Meshwork)
