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Won-Kyu Ju, Sang Yeop Kim, Myoung Sup Sim, Keun-Young Kim, Robert N Weinreb, Larry A Wheeler; Inhibition of cyclophilin D by cyclosporin A promotes retinal ganglion cell survival by preventing mitochondrial alteration in ischemic injury. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2431.
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© ARVO (1962-2015); The Authors (2016-present)
Cyclosporin A (CsA) inhibits the opening of the mitochondrial permeability transition pore (MPTP) by interacting with cyclophilin D (CypD) and ameliorates neuronal cell death in the central nervous system against ischemic injury. However, the molecular mechanisms underlying CypD/MPTP-mediated cell death in ischemic retinal injury remain unknown.
Transient retinal ischemia was induced by acute IOP elevation. Either vehicle or CsA treatment daily for 1 day before the induction of transient retinal ischemia and then continued vehicle or CsA (5mg/kg/day) treatment daily for 2 weeks. Retinal ganglion cell (RGC) survival was measured by immunohistochemstry for Brn3a. Apoptotic pathway was assessed by TUNEL staining and Western blot for cleaved caspase-3, Bcl-xL and phosphorylated Bad (pBad). Mitochondrial DNA (mtDNA) alteration were assessed by Western blot for mitochondrial transcription factor A (Tfam) and measurement for mtDNA content.
We observed the first direct evidence that CsA prevented the upregulation of CypD protein expression at 12h and promoted RGC survival against ischemic injury. Moreover, CsA blocked apoptotic cell death by decreasing cleaved caspase-3 protein expression in ischemic retina. Of interest, while the expression level of Bcl-xL protein did not show a significant change in ischemic retina treated with vehicle or CsA at 12 h, ischemic damage induced the reduction of Bcl-xL immunoreactivity in RGCs. More importantly, CsA preserved Bcl-xL immunoreactivity in RGCs of ischemic retina. In parallel, acute IOP elevation significantly increased phosphorylated Bad at Ser112 (pBad) protein expression in ischemic retina at 12 h. However, CsA significantly preserved pBad protein expression in ischemic retina. Finally, acute IOP elevation significantly increased Tfam protein expression in ischemic retina at 12 h. However, CsA significantly preserved Tfam protein expression in ischemic retina. Studies on mtDNA content in ischemic retina showed that there were no statistically significant differences in mtDNA content among control and ischemic groups treated with vehicle or CsA.
These results provide evidence that the activation of CypD-mediated MPTP opening is associated with apoptotic pathway and mitochondrial alteration in RGC death of ischemic retinal injury.
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