We investigated the role of methionine sulfoxide reductases (Msrs) in oxidant-stress-incluced cell death in retinal pigmented epithelial (RPE) cells. In RPE cells exposed to varying doses of H2O2, gene expression of MsrA and hCBS-1 (the human analog of MsrB2) increased in a dose-dependent and time-dependent manner with maximal increase with 150 mu M H2O2 in 24 h. H2O2 treatment resulted in the generation of reactive oxygen species and activation of caspase 3. Confocal microscopic and protein analysis showed an increase in MsrA expression in cytosol and mitochondria. Silencing of MsrA resulted in caspase 3 induction and accentuated cell death from H2O2. Focal, strong immuno reactivity for MsrA was observed in sub-RPE macular drusen from patients with age-related macular degeneration. In summary, our data show that MsrA and hCBS-1 are up-regulated in oxidative stress to counteract injury to RPE. (c) 2005 Elsevier Inc. All rights reserved.