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J.M. Gidday, Y. Zhang, B. Ojwang, Y. Zhu; Repetitive Hypoxic Preconditioning Leads to Sustained Elevations in Phosphorylated Akt and Hemoxygenase–1 in a Mouse Model of Long–Term Retinal Ischemic Tolerance . Invest. Ophthalmol. Vis. Sci. 2005;46(13):178.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: We showed previously in mice that repetitive hypoxic preconditioning (RHP) by six brief exposures to systemic hypoxia over a 2–week period provides a sustained protection against acute retinal ischemic injury for a period of up to 8 wks following the last preconditioning treatment (Gidday et al., ARVO 2003, #2942). In the present study, we assessed whether increases in PI3K/Akt pathway signaling and increases in the heat shock protein heme oxygenase–1 (HO–1) occur over a similarly protracted time period following RHP. Methods: Adult male Swiss–Webster ND4 mice were subjected to RHP as described earlier. At 0 h, 1 wk, 2 wks, and 4 wks after the last RHP treatment, eyes were rapidly enucleated, retinae were snap frozen, and whole cell lysates were prepared for immunoblotting for phosphorylated Akt (pAkt) and HO–1. Results: Running 3 samples from 6 animals (3 eyes) subjected to RHP, we found that pAkt levels were unchanged immediately after RHP relative to control eyes (n=5 samples from 10 animals; 20 eyes), but at 1 wk and 2 wks after RHP, levels were elevated by 3–fold, and remained elevated by 2–fold at 4 wks. With respect to HO–1, protein levels were elevated by 3–fold relative to control eyes immediately after and 1 wk after RHP, and showed a sustained 4–fold increase at both 2 wks and 4 wks after RHP. Conclusions: These results suggest that sustained elevations in survival–promoting pAkt–dependent signaling pathways and HO1–dependent cytoprotective effects may be responsible for the sustained state of ischemic tolerance in this model. The upstream, activating triggers and downstream targets of these two mediators, and their respective mechanisms of cytoprotection, while described in part in other systems, still require elucidation in this model.
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