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Transcriptional up-regulation and activation of initiating caspases in experimental glaucoma

Wei Huang1, Adam Dobberfuhl, Theodoros Filippopoulos

  • 1Howe Laboratory of Opthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA.

The American Journal of Pathology
|August 30, 2005
PubMed

Insights

Elevated intraocular pressure (IOP) in rats activates caspase 8 and caspase 9, initiating cell death in retinal ganglion cells (RGCs). This study reveals IOP triggers transcriptional changes leading to RGC apoptosis via both extrinsic and intrinsic pathways.

Area of Science:

  • Ophthalmology
  • Cell Biology
  • Molecular Biology

Background:

  • Glaucoma is characterized by retinal ganglion cell (RGC) apoptosis, often linked to elevated intraocular pressure (IOP).
  • The molecular mechanisms driving RGC apoptosis in response to increased IOP are not fully understood.

Purpose of the Study:

  • To investigate the expression and activation of initiator caspases (caspase 8 and caspase 9) in RGCs under elevated IOP conditions in a rat model.
  • To determine if elevated IOP induces transcriptional changes in RGCs affecting caspase expression.

Main Methods:

  • Rats were subjected to elevated IOP.
  • Cleaved forms of caspases, Bid, and PARP were analyzed to confirm caspase activation.
  • Laser capture microdissection was used to isolate RGCs.
  • Real-time polymerase chain reaction (PCR) was employed to measure mRNA levels of caspase 8 and caspase 9.

Main Results:

  • Elevated IOP led to the activation of both caspase 8 and caspase 9 in RGCs, evidenced by cleaved caspase forms and downstream targets.
  • A surprising increase in the procaspase 9 level was observed after 10 days of elevated IOP.
  • mRNA analysis revealed a specific increase in caspase 8 and caspase 9 mRNA levels within RGCs.

Conclusions:

  • Elevated IOP induces transcriptional up-regulation of initiating caspases (caspase 8 and caspase 9) in RGCs.
  • RGC apoptosis in glaucoma involves the activation of both extrinsic and intrinsic caspase cascades.
  • These findings highlight potential therapeutic targets for preventing RGC loss in glaucoma.

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