title: Verteporfin without light stimulation inhibits YAP activation in trabecular meshwork cells: Implications for glaucoma treatment.
abstract: Verteporfin, a photosensitizer, is used in photodynamic therapy to treat age-related macular degeneration. In a glaucoma mouse model, Verteporfin without light stimulation has been shown to reduce intraocular pressure (IOP) but the mechanism is unknown. Recent studies have shown that Verteporfin inhibits YAP without light stimulation in cancer cells. Additionally, YAP has emerged as an important molecule in the pathogenesis of glaucoma. We hypothesize that YAP inactivation by Verteporfin in trabecular meshwork (TM) may be related to the reduced IOP observed in vivo. As contractility of TM tissues is associated with IOP, collagen gel contraction assay was used to assess the effect of Verteporfin on contractility of TM cells. Human TM cells were embedded in collagen gel and treated with Verteporfin for 48 h. Areas of collagen gel sizes were quantified by ImageJ. To assess the effect of Verteporfin on the expression of YAP, human TM cells were treated with Verteporfin for 24 h and the expression of YAP was determined by Western blotting. To determine the cytotoxic effect of Verteporfin, human TM cells were treated with Verteporfin for 24 h, and then the cell viability was assessed by WST-1. We demonstrated here that Verteporfin (i) abolishes TM cell-mediated collagen gel contraction in a dose-dependent manner, (ii) attenuates expression of YAP and CTGF (connective tissue growth factor, a direct YAP target gene) in a dose-dependent manner, and (iii) has no significant cytotoxicity below 2 μM. Taken together, Verteporfin may facilitate aqueous humor outflow through the conventional outflow system and reduce IOP by inactivating YAP.
authors.affiliation: Program in Cell, Molecular & Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USA; New England Eye Center/Department of Ophthalmology, Tufts University, Boston, MA, USA.
authors.forename: Wei-Sheng
authors.initials: WS
authors.lastname: Chen
authors.affiliation: New England Eye Center/Department of Ophthalmology, Tufts University, Boston, MA, USA.
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Cao
authors.affiliation: New England Eye Center/Department of Ophthalmology, Tufts University, Boston, MA, USA.
authors.forename: Chandrasekharan
authors.initials: C
authors.lastname: Krishnan
authors.affiliation: Program in Cell, Molecular & Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USA; New England Eye Center/Department of Ophthalmology, Tufts University, Boston, MA, USA. Electronic address: Noorjahan.Panjwani@tufts.edu.
authors.forename: Noorjahan
authors.initials: N
authors.lastname: Panjwani
mesh_terms: D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D005901:Glaucoma / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects; D008027:Light; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017319:Photosensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D011166:Porphyrins / Q000494:pharmacology* / Q000627:therapeutic use; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077362:Verteporfin
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D017319:Photosensitizing Agents; D011166:Porphyrins; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D000077362:Verteporfin; D003094:Collagen
keywords: Glaucoma; Trabecular meshwork; Verteporfin; YAP