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Peroxiredoxins (PRDXs) contain a conserved cysteine residue(s) that undergoes a cycle of peroxide-dependent oxidation and thiol-dependent reduction during catalysis. Peroxiredoxin proteins are present in most living species requiring oxygen, and mammalian cells express six isoforms (PRDX1 to PRDX6) that are encoded by different nuclear genes. The relative abundance of peroxiredoxins in mammalian cells appears to protect cellular components by removing the low levels of peroxides produced as a result of normal cellular Peroxiredoxin V (PRDX5) is a member of the family of mammalian proteins that neutralize reactive oxygen species. The PRDX5 gene is constitutively expressed at a high level in many human tissues, but functional elements of its promoter responsible for a high basal activity in the absence of oxidative stress have still not been identified. Among predicted binding sites for transcription factors in the human PRDX5 promoter are binding sites for nuclear respiratory factor 1 (NFR-1) and nuclear respiratory factor 2 (also called GABPA), which regulate the biogenesis of mitochondria. We constructed luciferase reporter gene plasmids containing stepwise deletions of the PRDX5 promoter and examined their activities in transient transfections. Our results suggest that basal PRDX5 promoter activity mostly depends on NFR-1 and GABPA sites. The latter, in the PRDX5 promoter, were conserved in the six mammalian genomes analyzed (human, chimpanzee, cow, mouse, rat and dog) and a fraction of human PRDX5 associates with the mitochondrial matrix. We also found that the N-terminal 50 amino acids of the full-length human PRDX5 (24 kDa) translated from its first AUG codon targets this protein exclusively to mitochondria. However, the short form of PRDX5 (17 kDa), translated from its second AUG codon, has cytoplasmic and nuclear localization, which is also typical for endogenously expressed protein. Together, our results indicate that high basal expression of the PRDX5 gene is coordinated with the expression of nuclear genes encoding mitochondrial proteins and that the PRDX5 protein might play a major role in permanent defense against reactive oxygen species produced by mitochondria.Abbreviations cAMP, cyclic adenosine monophosphate; CREB, cAMP-response element binding protein; GFP, green fluorescent protein; NRF-1, nuclear respiratory factor 1; NRF-2, nuclear respiratory factor 2, also called GA-binding protein alpha (GABPA); PRDX, peroxiredoxin; TSS, transcription start site.

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These data are the first to identify an association between the ACE D-allele and DE in CCW. They provide evidence of a significant role for the RAS in the development of DE and suggest that clinical trials of ACE inhibition would be profitable in this group.