Disease relevance of Prdx6

• In this study, we evaluated whether genetic inactivation of Prdx6 in mice increases sensitivity to oxygen toxicity [1].
• After 72-h exposure to 100% O(2), lungs of Prdx6-/- mice showed more severe injury than wild-type with increased wet/dry weight, epithelial cell necrosis and alveolar edema on microscopic examination, increased protein and nucleated cells in BALF, and higher content of TBARS and protein carbonyls in lung homogenate [1].
• Since significant amounts of catalase and GSHPx are present in the heart contributing toward the attenuation of H(2)O(2) and hydroperoxides formed during ischemia-reperfusion injury and thereby providing cardioprotection, we asked whether Prdx6 also has any role in this process [2].
• Randomly selected hearts from Prdx6(-/-) mice and wild-type mice were subjected to 30 min of global ischemia followed by 120 min of reperfusion at normothermia [2].
• The hearts from the Prdx6(-/-) mice were more susceptible to ischemic reperfusion injury as evidenced by reduced recovery of left ventricular function, increased myocardial infarct size, and higher amount of apoptotic cardiomyocytes compared with wild-type mouse hearts [2].

High impact information on Prdx6

• Aging MTPa+/- mice had higher antioxidant activity of total SOD and GPx, lower GSH, and increased expression of cytochrome P-450 2E1, consistent with increased hepatic oxidative stress [3].
• In patients with chronic gastritis and gastric ulcers, the titer of CP3 antibody was significantly higher than in normal controls and correlated with the histological grade of antral gastritis [4].
• In conclusion, our results suggest that a moderate GPx increase can be sufficient to prevent irreversible functional damage produced by transient hypoxia in the hippocampus and to help maintain basic electrophysiological mechanisms involved in memory formation [5].
• Proteomic analyses of mouse brains by two-dimensional differential gel electrophoresis showed that several proteins, including growth hormone, 1-Cys peroxiredoxin, CCT-zeta, glucose-6-phosphate isomerase, GRP170 precursor, and alpha-SNAP, were differentially expressed [6].
• Using targeted inactivation of the Prdx6 gene, we present evidence that the corresponding protein offsets the deleterious effects of ROS on lens epithelial cells (LECs) and regulates gene expression by limiting its levels [7].

Chemical compound and disease context of Prdx6

• Thus, Prdx6 protects lungs against PQ toxicity as shown previously for hyperoxia, indicating that it functions as an important lung antioxidant enzyme [8].
• Recombinant human NSGPx expressed in Escherichia coli from a human cDNA clone (HA0683) showed GSH peroxidase activity with sn-2-linolenoyl- or sn-2-arachidonoyl-phosphatidylcholine hydroperoxides as substrate; NADPH or thioredoxin could not substitute for GSH [9].

Biological context of Prdx6

• However, overexpression of Prdx6 had no protective effect on LDL oxidation in vitro, and transgenic mice fed an atherogenic diet for 10 weeks did not possess an increased resistance to atherosclerosis nor did they maintain the high prediet plasma HDL levels consistent with the Ath1-resistant phenotype [10].
• We recently identified Prdx6 as a candidate for the quantitative trait locus Ath1, a gene responsible for a difference in diet-induced atherosclerosis susceptibility in mice [10].
• These Prdx6(-/-) hearts were also subjected to a higher amount of oxidative stress as evidenced by the presence of higher amount of malondialdehyde [2].
• Using Northern blotting with various Prdx6 probes, we have revealed the existence of multiple transcripts with distinct tissue distributions and regulation, including the major 1.4-kb transcript highly expressed in liver and lung, and two additional transcripts expressed primarily in liver [11].
• Mice have a highly related intronless gene (1-cysPrx-P1, GenBank accession number AF085220) with the same length of open reading frame (224 aa) as 1-cysPrx but located on a different chromosome [12].

Anatomical context of Prdx6

• Prdx6-/- macrophages had higher hydrogen peroxide levels, and lower survival rates; Prdx6-/- mice had significantly lower survival rates, more severe tissue damage, and higher protein oxidation levels [13].
• These mice expressed significantly elevated levels of Prdx6 mRNA and protein in multiple tissues including liver, aorta, and peritoneal macrophages, which accumulated significantly lower levels of hydrogen peroxide, revealing an enhanced antioxidant activity in these mice [10].
• Astrocytes contained peroxiredoxin 6, a unique nonredundant antioxidant [14].
• We studied changes in 1-cysPrx expression in rat lungs and lung cell lines in response to oxidative stress due to hyperoxia, H2O2, or paraquat [15].
• The frequency of bone marrow micronuclei, the extent of hepatic lipid peroxidation and the status of antioxidants-reduced glutathione (GSH), glutathione peroxidase (GPx) and glutathione-S-transferase (GST) were used as intermediate biomarkers of chemoprotection [16].

Associations of Prdx6 with chemical compounds

• Additionally, there were no differences in the mRNA expression levels of other peroxiredoxins, glutathione peroxidases, catalase, superoxide dismutases, thioredoxins, and glutaredoxins between normal Prdx6-/- and Prdx6+/+ mice and those injected with paraquat [13].
• These findings show that Prdx6 -/- mice have increased sensitivity to hyperoxia and provide in vivo evidence that Prdx6 is an important lung antioxidant enzyme [1].
• These results confirm an important role for Prdx6 in lung surfactant DPPC degradation and synthesis by the reacylation pathway [17].
• Degradation of internalized [3H]DPPC in isolated mouse lungs after endotracheal instillation of unilamellar liposomes labeled with [3H]DPPC was significantly decreased at 2 h in Prdx6-/- mice (13.6 +/- 0.3% vs. 26.8 +/- 0.8% in the wild type), reflected by decreased dpm in the lysophosphatidylcholine and the unsaturated PC fractions [17].
• Plasma lipid hydroperoxide levels were higher in atherogenic diet-fed Prdx6-/- mice with B6;129 and B6 backgrounds than in controls [18].

Physical interactions of Prdx6

• The gel shift assays showed that Sp1 and Pit-1a bind specifically to each binding site in 1-Cys Prx promoter [19].

Regulatory relationships of Prdx6

• We have previously identified and cloned a novel keratinocyte growth factor (KGF)-regulated gene in human keratinocytes that encodes the human homologue of a bovine non-selenium glutathione peroxidase (GPx) [20].

Other interactions of Prdx6

• Our study provides in vivo evidence that PRDX6 is a unique non-redundant antioxidant that functions independently of other peroxiredoxins and antioxidant proteins [13].
• In the 1-cysPrx 'knock-out' mouse, 1-cysPrx-P1 mRNA expression level was similar to the wild type but protein expression was not detected [12].
• However, we think it is unlikely that Prdx6 underlies Ath1 [18].
• There were no recombinants among 26 strains with Ly-22 and 1 recombinant among 24 strains with Ltw-4 [21].
• 1-Cys peroxiredoxin (1-cysPrx), a member of the peroxiredoxin family that contains a single conserved cysteine residue, reduces a broad spectrum of hydroperoxides [15].

Analytical, diagnostic and therapeutic context of Prdx6

• The normalized content of total phospholipid, phosphatidylcholine (PC), and disaturated phosphatidylcholine (DSPC) in bronchoalveolar lavage fluid, lung lamellar bodies, and lung homogenate was unchanged with age in wild-type mice but increased progressively in Prdx6-/- animals [17].
• Incorporation of [14C]palmitate into DSPC at 24 h after intravenous injection was decreased by 73% in lamellar bodies and by 54% in alveolar lavage surfactant in Prdx6-/- mice, whereas incorporation of [3H]choline was decreased only slightly [17].
• Through immunohistochemistry, we have determined that the PRDX6 protein was widely expressed in every tissue examined, most abundantly in epithelial cells [13].
• Since the product of this gene possibly could mimic 1-cysPrx function, we compared expression of 1-cysPrx and 1-cysPrx-P1 in mouse tissues by real-time polymerase chain reaction and Western blot [12].
• In situ hybridization studies demonstrated high levels of GPx mRNA in keratinocytes of the hyperproliferative epithelium at the wound edge [20].

References