Inhibition of cyclophilin D by cyclosporin A promotes retinal ganglion cell survival by preventing mitochondrial alteration in ischemic injury
| Autor: | Kim, SY, Shim, MS, Kim, K-Y, Weinreb, RN, Wheeler, LA, Ju, W-K |
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| Rok vydání: | 2014 |
| Předmět: |
Retinal Ganglion Cells
Time Factors genetic structures Cell Survival Oncology and Carcinogenesis bcl-X Protein Apoptosis mitochondrial DNA Inbred C57BL Eye Mitochondrial Membrane Transport Proteins mitochondrial transcription factor A Mice Cyclophilins Retinal Diseases Ischemia Animals Phosphorylation retinal ganglion cell Eye Disease and Disorders of Vision Intraocular Pressure Animal Caspase 3 Mitochondrial Permeability Transition Pore Prevention High Mobility Group Proteins retinal ischemia Neurosciences DNA eye diseases Mitochondria Mitochondrial DNA-Binding Proteins cyclosporin A Neuroprotective Agents Cytoprotection 5.1 Pharmaceuticals Disease Models Cyclosporine Ocular Hypertension Female bcl-Associated Death Protein sense organs Biochemistry and Cell Biology Development of treatments and therapeutic interventions cyclophilin D |
| Zdroj: | Cell death & disease, vol 5, iss 3 Kim, SY; Shim, MS; Kim, KY; Weinreb, RN; Wheeler, LA; & Ju, WK. (2014). Inhibition of cyclophilin D by cyclosporin A promotes retinal ganglion cell survival by preventing mitochondrial alteration in ischemic injury. Cell Death and Disease, 5(3). doi: 10.1038/cddis.2014.80. UC San Diego: Retrieved from: http://www.escholarship.org/uc/item/9032j22d |
| DOI: | 10.1038/cddis.2014.80. |
| Popis: | 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 opening-mediated cell death in ischemic retinal injury induced by acute intraocular pressure (IOP) elevation remain unknown. We observed the first direct evidence that acute IOP elevation significantly upregulated CypD protein expression in ischemic retina at 12 h. However, CsA prevented the upregulation of CypD protein expression and promoted retinal ganglion cell (RGC) survival against ischemic injury. Moreover, CsA blocked apoptotic cell death by decreasing cleaved caspase-3 protein expression in ischemic retina. Of interest, although 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 (pBad) at Ser112 protein expression in ischemic retina at 12 h. However, CsA significantly preserved pBad protein expression in ischemic retina. Finally, acute IOP elevation significantly increased mitochondrial transcription factor A (Tfam) protein expression in ischemic retina at 12 h. However, CsA significantly preserved Tfam protein expression in ischemic retina. Studies on mitochondrial DNA (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. Therefore, these results provide evidence that the activation of CypD-mediated MPTP opening is associated with the apoptotic pathway and the mitochondrial alteration in RGC death of ischemic retinal injury. On the basis of these observations, our findings suggest that CsA-mediated CypD inhibition may provide a promising therapeutic potential for protecting RGCs against ischemic injury-mediated mitochondrial dysfunction. © 2014 Macmillan Publishers Limited All rights reserved. |
| Databáze: | OpenAIRE |
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