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author:("Ran, qiao")
1.  Gpx4 ablation in adult mice results in a lethal phenotype accompanied by neuronal loss in brain 
Free radical biology & medicine  2012;52(9):1820-1827.
Glutathione peroxidase 4 (Gpx4) is an antioxidant defense enzyme important in reducing hydroperoxides in membrane lipids and lipoproteins. Gpx4 is essential for survival of embryos and neonatal mice; however, whether Gpx4 is required for adult animals remains unclear. In this study, we generated a floxed Gpx4 mouse (Gpx4(f/f)), in which exons 2–4 of Gpx4 gene are flanked by loxP sites. We then cross-bred the Gpx4(f/f) mice with a tamoxifen (tam)-inducible Cre transgenic mouse (R26CreER mice) to obtain mice in which the Gpx4 gene could be ablated by tam administration (Gpx4(f/f)/Cre mice). After treatment with tam, adult Gpx4(f/f)/Cre mice (6–9 months of age) showed a significant reduction of Gpx4 levels (a 75–85 % decrease) in tissues such as brain, liver, lung and kidney. Tam-treated Gpx4(f/f)/Cre mice lost body weight and died within 2 weeks, indicating that Gpx4 is essential for survival of adult animals. Tam-treated Gpx4(f/f)/Cre mice exhibited increased mitochondrial damage, as evidenced by the elevated 4-hydroxylnonenal (4-HNE) level, decreased activities of electron transport chain complex I and IV, and reduced ATP production in liver. Tam treatment also significantly elevated apoptosis in Gpx4(f/f)/Cre mice. Moreover, tam-treated Gpx4(f/f)/Cre mice showed neuronal loss in hippocampus region and had increased astrogliosis. These data indicate that Gpx4 is essential for mitochondria integrity and survival of neurons in adult animals.
doi:10.1016/j.freeradbiomed.2012.02.043
PMCID: PMC3341497  PMID: 22401858
Gpx4; knockout mice; lipid peroxidation; mitochondria; neurodegeneration; apoptosis; oxidative stress
2.  Dietary fish oil promotes colonic apoptosis and mitochondrial proton leak in oxidatively stressed mice 
An alteration of mitochondrial function can result in disruption of redox homeostasis, and is associated with abnormal cancer cell growth. Manganese superoxide dismutase (SOD2) and glutathione peroxidase 4 (Gpx4) are two of the most important antioxidant defense enzymes that protect cells against oxidative stress. We have previously shown that n-3 polyunsaturated fatty acids (PUFA) promote colonocyte apoptosis, a marker of colon cancer risk, in part by enhancing phospholipid oxidation. To elucidate the mechanisms regulating oxidative stress-induced apoptosis in vivo, we fed heterozygous SOD2Het, Gpx4Het and transgenic Gpx4TG mice diets containing either 15% corn oil by weight (CO, enriched in n-6 PUFA) or 3.5% CO + 11.5% fish oil (FO, enriched in n-3 PUFA) for 4 wk. Our data show that (i) genetic pre-deposition to oxidative stress facilitates apoptosis in the mouse colon (Gpx4Het > SOD2Het > Wt > Gpx4Tg), (ii) dietary n-3 PUFA have an additive effect on the induction of apoptosis in Gpx4Het and SOD2Het mice; and (iii) dietary n-3 PUFA reverse the phenotype in oxidatively protected Gpx4Tg mice by elevating apoptosis to a level observed in wild type (control) animals. Complimentary experiments examining colonic mitochondrial bioenergetic profiles indicate that FO fed mice exhibit a significantly (p<0.05) increased respiration-induced proton leak relative to control CO treatment. This finding is consistent with a loss of membrane potential in response to chronic oxidative stress, and supports the contention that n-3 PUFA alter mitochondrial metabolic activity, thereby enhancing apoptosis and reducing colon cancer risk.
doi:10.1158/1940-6207.CAPR-10-0368
PMCID: PMC3137683  PMID: 21490130
apoptosis; n-3 PUFA; oxidation; colon; mitochondria
3.  COLLAGEN MUTATION CAUSES CHANGES OF THE MICRODAMAGE MORPHOLOGY IN BONE OF AN OI MOUSE MODEL 
Bone  2010;47(6):1071-1075.
Previous studies have postulated that ultrastructural changes may alter the pattern and capacity of microdamage accumulation in bone. Using an osteogenesis imperfecta (OI) mouse model, this study was performed to investigate the correlation of collagen mutation with the microdamage morphology and the associated brittleness of bone. In this study, femurs from mild OI and wild type mice were fatigued under four-point bending to create microdamage in the specimens. Then, the microdamage morphology of these specimens was examined using the bulk-staining technique with basic fuchsin. Similar with the results of previous studies, it was observed that linear microcracks were formed more easily in compression, whereas diffuse damage was induced more readily in tension for both wild-type and mild-type mice. However, less diffuse damage was found in the tensile side of mild OI mouse femurs (collagen mutation) compared with those of wild type mice, showing that the microdamage morphology is correlated to the brittleness of bone. The results of this study provide direct evidence that supports the prediction made by the previous numerical simulation studies, suggesting that microdamage morphology in bone is significantly correlated with the integrity of the collagen phase.
doi:10.1016/j.bone.2010.08.013
PMCID: PMC2970676  PMID: 20736092
Linear microcrack; diffuse damage; collagen mutation; osteogenesis imperfecta; fatigue
4.  Is the Oxidative Stress Theory of Aging Dead? 
Biochimica et biophysica acta  2009;1790(10):1005-1014.
Currently, the Oxidative Stress (or Free Radical) Theory of Aging is the most popular explanation of how aging occurs at the molecular level. While data from studies in invertebrates (e.g., C. elegans and Drosophila) and rodents show a correlation between increased lifespan and resistance to oxidative stress (and in some cases reduced oxidative damage to macromolecules), direct evidence showing that alterations in oxidative damage/stress play a role in aging are limited to a few studies with transgenic Drosophila that overexpress antioxidant enzymes. Over the past eight years, our laboratory has conducted an exhaustive study on the effect of under- or overexpressing a large number and wide variety of genes coding for antioxidant enzymes. In this review, we present the survival data from these studies together. Because only one (the deletion of the Sod1 gene) of the 18 genetic manipulations we studied had an effect on lifespan, our data calls into serious question the hypothesis that alterations in oxidative damage/stress play a role in the longevity of mice.
doi:10.1016/j.bbagen.2009.06.003
PMCID: PMC2789432  PMID: 19524016
Antioxidant defense; oxidative stress; oxidative damage; knockout mice; transgenic mice; longevity
5.  Glutathione Peroxidase 4 Differentially Regulates the Release of Apoptogenic Proteins from Mitochondria 
Free radical biology & medicine  2009;47(3):312-320.
Glutathione peroxidase 4 (Gpx4) is a unique antioxidant enzyme that repairs oxidative damage to biomembranes. In the present study, we examined the effect of Gpx4 on the release of various apoptogenic proteins from mitochondria using transgenic mice overexpressing Gpx4 [Tg(GPX4+/0)] and mice deficient in Gpx4 (Gpx4+/− mice). Diquat exposure triggered apoptosis that occurred through intrinsic pathway and resulted in the mitochondrial release of cytochrome c (cyt. c), Smac/DIABLO, and Omi/HtrA2 in the liver of wild-type (Wt) mice. Liver apoptosis and cyt. c release were suppressed in Tg(GPX4+/0) mice but exacerbated in Gpx4+/− mice; however, neither the Tg(GPX4+/0) nor the Gpx4+/− mice showed any alterations in the levels of Smac/DIABLO or Omi/HtrA2 released from mitochondria. Submitochondrial fractionation data showed that Smac/DIABLO and Omi/HtrA2 existed primarily in the intermembrane space and matrix, while cyt. c and Gpx4 were both associated with inner membrane. In addition, diquat exposure induced cardiolipin peroxidation in the liver of Wt mice; the levels of cardiolipin peroxidation were reduced in Tg(GPX4+/0) mice but elevated in Gpx4+/− mice. These data suggest that Gpx4 differentially regulates apoptogenic protein release due to its inner membrane location in mitochondria and its ability to repair cardiolipin peroxidation.
doi:10.1016/j.freeradbiomed.2009.05.012
PMCID: PMC2773016  PMID: 19447173
Gpx4; Phospholipid hydroperoxide glutathione peroxidase 4; Apoptosis; Cardiolipin; Lipid peroxidation; Oxidative stress
6.  Lipid peroxidation upregulates BACE1 expression in vivo: a possible early event of amyloidogenesis in Alzheimer’s disease 
Journal of neurochemistry  2008;107(1):197-207.
Increased lipid peroxidation is shown to be an early event of AD. However, it is not clear whether and how increased lipid peroxidation might lead to amyloidogenesis, a hallmark of AD. Gpx4 is an essential antioxidant defense enzyme that protects an organism against lipid peroxidation. Gpx4+/- mice show increased lipid peroxidation in brain, as evidenced by their elevated levels of 4-HNE. To understand the role of lipid peroxidation in amyloidogenesis, we studied secretase activities in Gpx4+/- mice as a function of age. Both young (6-month) and middle-aged (17- to 20- month) Gpx4+/- mice had higher levels of β-secretase activity than their age-matched wildtype controls, and the increased β-secretase activity in Gpx4+/- mice was a result of upregulation of BACE1 expression at the protein level. The high level of BACE1 protein led to increased endogenous Aβ1-40 in middle-aged Gpx4+/- mice. We further studied amyloidogenesis in APPGpx4+/- mice. Our data indicate that APPGpx4+/- mice had significantly increased amyloid plaque burdens and increased Aβ1-40 and Aβ1-42 levels compared to APPGpx4+/+ mice. Therefore, our results indicate that increased lipid peroxidation leads to increased amyloidogenesis through upregulation of BACE1 expression in vivo, a mechanism that may be important in pathogenesis of AD at early stages.
doi:10.1111/j.1471-4159.2008.05603.x
PMCID: PMC2716044  PMID: 18680556
Lipid peroxidation; Alzheimer’s disease; BACE1; glutathione peroxidase 4; Aβ; APP transgenic mice
7.  Suppression of Atherogenesis by Overexpression of Glutathione Peroxidase-4 in Apolipoprotein E-Deficient Mice 
Free radical biology & medicine  2007;44(3):343-352.
Accumulation of oxidized lipids in the arterial wall contributes to atherosclerosis. Glutathione peroxidase-4 (GPx4) is a hydroperoxide scavenger that removes oxidative modifications from lipids such as free fatty acids, cholesterols, and phospholipids. Here, we set out to assess the effect of GPx4 overexpression on atherosclerosis in apolipoprotein E-deficient (ApoE−/−) mice. The results revealed that atherosclerotic lesions in the aortic tree and aortic sinus of ApoE−/− mice overexpressing GPx4 (hGPx4Tg/ApoE−/−) were significantly smaller than those of ApoE−/− control mice. GPx4 overexpression also diminished signs of advanced lesions in the aortic sinus, as seen by a decreased occurrence of fibrous caps and acellular areas among hGPx4Tg/ApoE−/− animals. This delay of atherosclerosis in hGPx4Tg/ApoE−/− mice correlated with reduced aortic F2-isoprostane levels (R2 = 0.75, p < 0.01). In addition, overexpression of GPx4 lessened atherogenic events induced by the oxidized lipids, lysophosphatidylcholine and 7-ketocholesterol, including upregulated expression of adhesion molecules in endothelial cells, adhesion of monocytes to endothelial cells, as well as endothelial necrosis and apoptosis. These results suggest that overexpression of GPx4 inhibits the development of atherosclerosis by decreasing lipid peroxidation and inhibiting the sensitivity of vascular cells to oxidized lipids.
doi:10.1016/j.freeradbiomed.2007.09.009
PMCID: PMC2245803  PMID: 18215741
Glutathione peroxidase-4; Atherosclerosis; Lipid peroxidation; Monocyte adhesion; Necrosis; Apoptosis

Results 1-7 (7)