Long-term tolerance to retinal ischemia by repetitive hypoxic preconditioning:: Role of HIF-1α and heme oxygenase-1

PURPOSE. To determine whether the duration of ischemic tolerance in the retina could be extended by repetitive presentations of the preconditioning stimulus and to begin to elucidate the mechanistic underpinnings of the resultant novel phenotype. METHODS. Adult male Swiss-Webster ND4 mice were repeatedly preconditioned with systemic hypoxia (RUP) over 12 days; 4 weeks later, the mice were subjected to 30 minutes of unilateral retinal ischemia. Protection was quantified morphologically and functionally I week after ischemia by histologic analyses and scotopic electroretinography, respectively. Temporal expression patterns of hypoxia-inducible factor (HIF)-1 alpha and heme oxygenase (HO)-1 were measured in response to RHP and after retinal ischemia by immunoblot analysis and immunohistochemistry. RESULTS. Morphologic and functional protection against ischemia-induced reductions in retinal layer thicknesses and layer cell counts, and a- and b-wave amplitudes, was documented for at least 4 weeks after RHP. There was no evidence of tissue injury or dysfunction by RHP alone. Temporally associated with this period of long-term tolerance (LTT) to retinal ischemia were sustained increases in retinal levels of HIF-1 alpha and HO-1 protein lasting at least 1 and 4 weeks, respectively, after the last RHIP stimulus. CONCLUSIONS. A novel form of sustained retinal ischemic tolerance is described, wherein endogenous adaptive responses triggered by repeated hypoxia afford protection against injury many weeks after the preconditioning stimulus. HIF-1 alpha -mediated, long-lasting increases in retinal HO-1 expression may contribute to the LTT phenotype. Further elucidation of the genetic and molecular basis of such adaptive plasticity could provide therapeutic targets for preventing and/or treating a variety of ischemic retinopathies.