April 2011
Volume 52, Issue 14
ARVO Annual Meeting Abstract  |   April 2011
Effects Of Gleevec And Nilotinib On Trabecular Meshwork PILS And Outflow Facility
Author Affiliations & Notes
  • Mini Aga
    Ophthalmology, Casey Eye Institute/OHSU, Portland, Oregon
  • John M. Bradley
    Ophthalmology, Casey Eye Institute/OHSU, Portland, Oregon
  • Kaili Song
    Ophthalmology, Casey Eye Institute/OHSU, Portland, Oregon
  • Mary J. Kelley
    Ophthalmology, Casey Eye Institute/OHSU, Portland, Oregon
  • Ted Acott
    Ophthalmology, Casey Eye Institute/OHSU, Portland, Oregon
  • Footnotes
    Commercial Relationships  Mini Aga, None; John M. Bradley, None; Kaili Song, None; Mary J. Kelley, None; Ted Acott, None
  • Footnotes
    Support  NIH #EY008247, #EY003279, #EY010572 and an unrestricted grant from Research to Prevent Blindness.
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 4644. doi:
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      Mini Aga, John M. Bradley, Kaili Song, Mary J. Kelley, Ted Acott; Effects Of Gleevec And Nilotinib On Trabecular Meshwork PILS And Outflow Facility. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4644.

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

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Purpose: : Podosome- or invadopodia-like structures (PILS) are specialized adhesion and degradation units involved in extracellular matrix turnover in the trabecular meshwork (TM). To better understand PILS organization and involvement in modulating aqueous humor outflow facility, the effects of Gleevec and Nilotihib, which are Abl and Arg tyrosine kinase inhibitors, were evaluated.

Methods: : Studies were conducted using cultured porcine and human TM cells, and perfused anterior segments. Effects of mechanical stretch, Gleevec and Nilotinib on PILS component localization were determined by confocal microscopy. Perfused anterior segments were subjected to elevated perfusion pressure and these inhibitors and the effect on outflow facility was determined.

Results: : Mechanical stretch, Gleevec, and Nilotinib alter PILS organization and the association of cortactin, a PILS marker, with MMP2, MMP14, and α-tubulin. PILS became more diffuseand lattice-like after inhibitor treatment. Microtubules in PILS became more pronounced, appearing to encase small circular vesicles. Several endosomal markers (RAB4, LAMP1 and LAMP2) normally colocalized with PILS components and treatment with Gleevec or Nilotinib increased this association in the lattice-like PILS. Higher doses of inhibitors produced enhanced perinuclear aggresome-like vesicles within vimentin cages. TM cells transfected with dominant negative RhoA also changed PILS patterns and organization. Gleevec inhibited phosphorylation of Abl, but increased Erk 1/2 phosphorylation. Inhibition of Erk 1/2 activation by U0126 produced denser and more numerous PILS. Perfusion of human or porcine anterior segments with Gleevec or Nilotinib decreased outflow facility at 24-72 hours and more dramatically reduced the normal homeostatic correction to increasing perfusion pressure.

Conclusions: : Gleevec or Nilotinib change the organization of TM cell PILS, shifting some components to other PILS forms. Both inhibitors reduce outflow facility and diminish the homeostatic response to pressure elevation. Abl and/or Arg, Erk 1/2, and RhoA appear to be components of pathway(s) regulating these effects.

Keywords: trabecular meshwork • outflow: trabecular meshwork • cytoskeleton 

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