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Y. Zhu, M. Bielinska, J.M. Gidday; Sustained Elevations in Thioredoxin and Adrenomedullin mRNA Levels in Retina Following Repetitive Hypoxic Preconditioning: Role in Ischemic Tolerance? . Invest. Ophthalmol. Vis. Sci. 2006;47(13):499.
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© ARVO (1962-2015); The Authors (2016-present)
We previously reported that preconditioning adult mice with a single period of brief systemic hypoxia protects against retinal ischemic injury (Zhu et al., IOVS 43:1903–1911, 2002). Subsequently, we showed that repetitive hypoxic preconditioning (RHP), which consisted of six exposures of mice to systemic hypoxia over a 2–week period, provided robust protection against acute retinal ischemic injury that was sustained at least 4 weeks following the last preconditioning treatment (Gidday et al., ARVO 2003, #2942). In an effort to elucidate the mechanistic basis of this protracted neuroprotective phenotype, we examined temporal changes in mRNA expression in response to RHP for two unique cytoprotective proteins. One was thioredoxin, a stress–inducible, redox–regulating disulfide reductase protein that regulates gene transcription, scavenges free radicals, and inhibits apoptosis; the other was adrenomedullin, a HIF–1α gene target that exhibits anti–apoptotic and anti–oxidant effects, vasodilates arterioles, and is proangiogenic.
Adult male Swiss–Webster ND4 mice were subjected to RHP as described earlier. At 4 h, 24 h, 1 wk, 2 wks, and 4 wks after the last RHP treatment, eyes were rapidly enucleated, and RNA was extracted from both eyes for reverse–transcriptase PCR. Age and sex–matched mice not subjected to RHP were used as controls.
Analysis of RT–PCR products indicated that mRNA levels for thioredoxin were elevated at all timepoints after RHP. The peak response was at 24 h, but high levels were also found 2 wks after RHP; thioredoxin mRNA expression levels at 4 h, 1 wk, and 4 wks after RHP were still elevated above control. For adrenomedullin, mRNA levels were elevated at 4 h and 24 h after RHP, but the highest expression was found 2 wks after RHP. mRNA levels 1 wk and 4 wks after RHP were only modestly elevated above control.
These results show that sustained changes in message levels of two putative neuroprotective proteins occur in response to the RHP stimulus, and serve as evidence of a unique adaptive plasticity in the retina in response to repetitive hypoxic stress. Although prolonged upregulation at the protein level has not yet been documented, protracted changes in the expression of genes that encode for these unique cytoprotective proteins may contribute to the ability of RHP to afford long–lasting tolerance to retinal ischemia.
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