title: Rho GTPase signaling promotes constitutive expression and release of TGF-β2 by human trabecular meshwork cells.
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)-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.
authors.affiliation: 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.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Pervan
authors.affiliation: Research Service, Department of Veterans Affairs, Edward Hines Jr. VA Hospital, Hines, IL, USA; Program in Neuroscience, Loyola University Chicago, Maywood, IL, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Lautz
authors.affiliation: Research Service, Department of Veterans Affairs, Edward Hines Jr. VA Hospital, Hines, IL, USA; Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Blitzer
authors.affiliation: Research Service, Department of Veterans Affairs, Edward Hines Jr. VA Hospital, Hines, IL, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Langert
authors.affiliation: Research Service, Department of Veterans Affairs, Edward Hines Jr. VA Hospital, Hines, IL, USA; Department of Ophthalmology, Loyola University Chicago, Maywood, IL, USA; Program in Neuroscience, Loyola University Chicago, Maywood, IL, USA.
authors.forename: Evan B
authors.initials: EB
authors.lastname: Stubbs
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D005902:Glaucoma, Open-Angle / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007429:Intraocular Pressure; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D013552:Swine; D014129:Trabecular Meshwork / Q000378:metabolism* / Q000473:pathology; D053781:Transforming Growth Factor beta2 / Q000096:biosynthesis / Q000235:genetics*; D020741:rho GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D053781:Transforming Growth Factor beta2; D012313:RNA; D020741:rho GTP-Binding Proteins
keywords: Glaucoma; Intraocular pressure; Rho GTPase; TGF-β2; Trabecular meshwork