July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
Prostaglandin analogue and beta blocker combination treatment facilitates anti-fibrotic environment in trabecular meshwork of glaucoma patients by regulating SMAD-dependent signaling
Author Affiliations & Notes
  • Praveen Machiraju
    GROW Research Laboratory, Narayana Nethralaya Foundation, Bengaluru, Karnataka, India
  • Sushma Tejwani
    Glaucoma services, Narayana Nethralaya, Bengaluru, Karnataka, India
  • Anuprita Ghosh
    GROW Research Laboratory, Narayana Nethralaya Foundation, Bengaluru, Karnataka, India
  • Swaminathan Sethu
    GROW Research Laboratory, Narayana Nethralaya Foundation, Bengaluru, Karnataka, India
  • Arkasubhra Ghosh
    GROW Research Laboratory, Narayana Nethralaya Foundation, Bengaluru, Karnataka, India
  • Footnotes
    Commercial Relationships   Praveen Machiraju, None; Sushma Tejwani, None; Anuprita Ghosh, None; Swaminathan Sethu, None; Arkasubhra Ghosh, None
  • Footnotes
    Support  Narayana Nethralaya Foundation
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 3778. doi:
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      Praveen Machiraju, Sushma Tejwani, Anuprita Ghosh, Swaminathan Sethu, Arkasubhra Ghosh; Prostaglandin analogue and beta blocker combination treatment facilitates anti-fibrotic environment in trabecular meshwork of glaucoma patients by regulating SMAD-dependent signaling. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3778.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Anti-glaucoma medications (AGM) reduce raised intraocular pressure (IOP) by regulating aqueous outflow but their effect on the trabecular meshwork (TM) is not fully understood. The purpose of the study was to determine the effect of prostaglandin analogue (PG), beta blocker (BB) and their combination (PG-BB) on the fibrotic status of TM of primary glaucoma patients and to elucidate the underlying molecular mechanisms.

Methods : TM tissues were obtained from primary glaucoma patients (Primary open angle, POAG, n=32 and closed angle, PACG, n=37) during trabeculectomy , following informed consent from study subjects and prior ethics committee approval. Subjects were grouped as PG, BB and PG-BB based on AGM history. Expression of pro-fibrotic (TGFβ1, TGFβ2, TGFβR2, CTGF, Fibronectin (FN), LOXL2, Wnt3A) and anti-fibrotic (Hevin, Decorin) genes were measured using qPCR in TM. Further, primary cultured TM cells were treated in vitro with PG, BB or PG-BB to mechanistic validation by measuring gene expression (qPCR), protein expression and intracellular signaling (western blotting) and secretory factors (multiplex ELISA).

Results : Reduced expression of TGFβ1, TGFβ2, TGFβR2, CTGF*, FN*, LOXL2* and Wnt3A expression (*p<0.05) was found in TM of patients on PG-BB than those on PG or BB. FN showed a significant decrease in PG-BB group (0.013 ± 0.003) as compared to BB (0.052 ± 0.01), whereas, CTGF was significantly reduced in PG-BB (0.320 ± 0.15) compared to PG (1.084 ± 0.35) or BB (0.687 ± 0.48) treatment groups. Gene expression analysis from in-vitro experiments showed similar reduction in fibrosis-associated genes upon combination treatment. Decreased protein levels of FN and CTGF in whole cell lysates were observed in PG-BB treatment, compared to PG or BB. Protein levels of TGFβ family signaling mediator, SMAD2/3 and phospho-SMAD3 were reduced in PG-BB treatment. PG-BB treatment increased the level of MMP9 (3.6 fold vs PG, 2.1 fold vs BB) and decreased the level of MMP2 (-1.2 fold vs PG, -1.4 fold vs BB) without any change in the levels of TGFβ in TM cell culture supernatants.

Conclusions : Anti-glaucoma medication directly affects fibrotic status of TM. In addition to its intended role on IOP reduction, PG-BB combination can also provide a reduced profibrotic environment in TM for better prognosis in glaucoma patients.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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