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B. D. Quill, N. G. Docherty, D. M. Wallace, C. J. O'Brien, A. F. Clark; Verapamil Blocks Mechanical Strain Induced Upregulation of TGF-β1 mRNA in Lamina Cribrosa Cells. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3168.
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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. Transforming growth factor beta 1 (TGF-1) 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 (V), on mechanical stretch induced TGF-1 upregulation in LC cells from the optic nerve head of glaucomatous (GLC) and non-glaucomatous donors (NLC).
Confluent LC cell cultures were serum starved for 24h, then exposed to cyclical mechanical stretch (15%, 1Hz) for 24h in the presence or absence of V (10mM). TGF-1 mRNA levels were assessed by real time RT-PCR.
In NLC, treatment with V caused no change in TGF-1 mRNA levels under baseline (static) conditions. Following exposure to mechanical strain, TGF-1 mRNA levels were increased 1.6 fold (p=0.02). This response did not occur in the presence of V, with TGF-1 mRNA levels falling below baseline static levels (1.6 v’s 0.7, p=0.03). No stretch induced alteration in TGF-1 mRNA levels was observed in GLC. However, a significant 35% decrease in TGF-1 mRNA levels was observed in GLC in the presence of V (p<0.01).
This study demonstrates that mechanical stretch induced upregulation of TGF-1 expression involves the activation of L-type channel derived calcium currents. 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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