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J. Gidday, B. K. McMahan, S. Dore, Y. Zhu; Pharmacologic Blockade or Genetic Deletion of Heme Oxygenase-1 Expression in Adult Mice Abrogates Retinal Ischemic Tolerance Induced by Hypoxic Preconditioning. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2065. doi: https://doi.org/.
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Recent studies by our lab (Zhu Y, IOVS 48: 1735-1743, 2007) and others document changes in retinal heme oxygenase-1 (HO-1) expression in response to various forms of stress (hypoxia, oxidative), and ischemia as well. To test the hypothesis that the pleiotropic cytoprotective effects of HO-1 (anti-inflammatory, anti-apoptotic, vasodilatory) contribute to retinal neuroprotection following hypoxic preconditioning (HPC), we assessed (1) whether pharmacologic inhibition of HO-1 with zinc protoporphyrin IX (ZnPPIX) would affect the ability of SHP to protect against retinal ischemia; and (2) to what extent HPC-induced ischemic tolerance would be affected in HO-1 mutant mice.
Two studies were conducted in adult male mice subjected to 30-min retinal ischemia by intraocular pressure elevation, as described previously (Zhu et al., IOVS, 2007). In one study, SW-ND4 mice were subjected to HPC (2h of 11% oxygen) two days before ischemia; half of these mice received 25 mg/kg ZnPPIX (25 mg/kg ip) 1 h before ischemia. In a parallel study, HO-1 homozygous null mice, and strain-matched wild-types, were rendered ischemic, with half of the mice from each group receiving HPC prior to ischemia. One week after ischemia, eyes were enucleated, embedded in paraffin, and the number of cells in the retinal ganglion cell (RGC) layer and inner nuclear cell layer (INL) was quantified in thin sections at set distances from the optic nerve. Comparisons between eyes and between groups (n=4-5) by nonparametric statistics, with p<0.05 as significant.
Thirty min of retinal ischemia resulted in significant cell loss (20-25%) in the INL and GCL, in addition to thinning of the INL, inner plexiform layer, and entire retinal thickness. With SHP, cell loss in the INL was negligible, and cell loss in the GCL was only 12%. Inhibition of HO-1 during and after ischemia with ZnPPIX significantly blocked the protective effects of SHP with respect to cell salvage in the INL and GCL. And the protection afforded by SHP in HO-1 wildtype mice was not achieved in either retinal cell layer in HO-1 knockouts.
These pharmacologic and genetic findings provide cross-validating support for the hypothesis that HO-1 activity, particularly during and following ischemia, is critical to establishing the ischemia-tolerant phenotype following hypoxic preconditioning. The exact mechanisms whereby HO-1 protects these cells requires elucidation.
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