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Barry Quill, Neil Docherty, Elizabeth M. McElnea, Deborah Wallace, Abbot F. Clark, Colm J. O'Brien; Calcium Regulation Of Strain Induced Extracellular Matrix Genes In Lamina Cribrosa Cells. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5325.
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Mechanical stress as a result of elevations in intra-ocular pressure is a key environmental stimulus for extracellular matrix (ECM) remodelling of the lamina cribrosa (LC) in glaucoma. TGF-β1 is a driver of this response. Transient increases in intracellular calcium are implicated in the cellular response to mechanical stretch, including the activation of an altered transcriptional profile in affected cells. This study examined the effect of the L-type calcium channel blocker verapamil, on mechanical stretch induced ECM genes in LC cells from the optic nerve head of glaucomatous (GLC) and non-glaucomatous donors (NLC).
Confluent LC cell cultures, from normal and glaucomatous donors, were serum starved for 24h prior to exposure to cyclical mechanical stretch (15%) for 24h in the presence or absence of Verapamil (10mM). TGF-β1, Collagen VI (COLVI) and chondroitin sulphate proteoglycan (CSPG) mRNA levels were assessed by RT-PCR.
In NLC cells, 15% strain provoked a statistically significant transcriptional responses in all genes examined. In NLC, following exposure to mechanical strain, TGF-β1 mRNA levels were increased 1.6 fold. This response did not occur in the presence of Verapamil, with TGF-β1 mRNA levels falling below baseline static levels (1.6 v’s 0.7 fold). CSPG and COLVI showed a similar response to strain and Verapamil. No stretch induced alteration in TGF-β1 mRNA levels was observed in GLC. However, a significant 35% decrease in TGF-β1 mRNA levels was observed in GLC in the presence of Verapamil. In GLC, CSPG was up regulated by 15% strain (4.378+/-0.794 fold). This response did not occur in the presence of Verapamil as transcriptional levels fell by almost 3 fold (4.76+/-0.86 Versus 1.839+/-0912 fold). A significant difference in transcriptional levels of COLLAGEN VIA3 was seen in a static environment (NLC 1.10+/-0.61 fold V’s GLC 3.14+/-0.60 fold). In GLC, 15% strain induced a greater than 2 fold decrease in expression of Collagen VIA3 mRNA (0.374+/- 0.029 fold).
This study provides intriguing evidence of a novel mechano-transduction pathway linking stretch, cation channel functions and the induction of LC cell gene transcription. This highlights the potential involvement of calcium transients in the activation of remodelling responses in the optic nerve head glia and supports the rationale that calcium channel blockers may directly attenuate disease progression in glaucoma.
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