An imbalance in antioxidant defense affects cellular function: the pathophysiological consequences of a reduction in antioxidant defense in the glutathione peroxidase-1 (Gpx1) knockout mouse

Haan, Judy B. de; Crack, Peter J; Flentjar, Nicole J; Iannello, Rocco C.; Hertzog, Paul J.; Kola, Ismail

doi:10.1179/135100003125001378

Cited by 82 publications

(48 citation statements)

References 81 publications

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“…However, when these mice were exposed to ionizing radiation, Sod1 transgenic mice developed smaller lesions than control animals (37). Interestingly, the increased removal of superoxide anion radicals resulting from the overexpression of Sod1 is expected to increase cellular H 2 O 2 (38). Thus, in both our model (22) and the Sod1 transgenic model (37), increased cellular H 2 O 2 is associated with decreased atherosclerosis in C57BL/6J mice fed a HFD.…”

Section: Discussionmentioning

confidence: 91%

Lack of the antioxidant glutathione peroxidase-1 does not increase atherosclerosis in C57BL/J6 mice fed a high-fat diet

Witting

Stefanovic

Pete

et al. 2006

Journal of Lipid Research

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Oxidative stress is thought to contribute to the initiation and progression of atherosclerosis. As glutathione peroxidase-1 (Gpx1) is an antioxidant enzyme that detoxifies lipid hydroperoxides, we tested the impact of Gpx1 deficiency on atherosclerotic processes and antioxidant enzyme expression in mice fed a high-fat diet (HFD). After 12 weeks of HFD, atherosclerotic lesions at the aortic sinus were of similar size in control and Gpx1-deficient mice. However, after 20 weeks of HFD, lesion size increased further in control but not in Gpx1-deficient mice, even though plasma and aortic wall markers of oxidative damage did not differ between groups. In control mice, the expression of Gpx1 increased and that of Gpx3 decreased at the aortic sinus after 20 weeks of HFD, with no change in the expression of Gpx2, Gpx4, catalase, peroxiredoxin-6, glutaredoxin-1 and -2, or thioredoxin-1 and -2. By comparison, in Gpx1-deficient mice, the expression of antioxidant genes was unaltered except for a decrease in glutaredoxin-1 and an increase in glutaredoxin-2. These changes were associated with increased expression of the proinflammatory marker monocyte chemoattractant protein-1 in control mice but not in Gpx1-deficient mice. In summary, a specific deficiency in Gpx1 was not accompanied by an increase in markers of oxidative damage or increased atherosclerosis in a murine model of HFD-induced atherogenesis.-de Haan,

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Section: Discussionmentioning

confidence: 91%

Lack of the antioxidant glutathione peroxidase-1 does not increase atherosclerosis in C57BL/J6 mice fed a high-fat diet

Witting

Stefanovic

Pete

et al. 2006

Journal of Lipid Research

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“…Similarly, the GSH synthesis inhibitor buthionine sulfoximine (BSO) potentiated MPTP toxicity in mice (199). Furthermore, MPTP treatment depleted brainstem GSH (204), and mice deficient in Gpx-1 exhibited increased vulnerability to MPTP (37) .…”

Section: Oxidative Stress As a Disruption Of Redox Signaling And Controlmentioning

confidence: 99%

Radical-free biology of oxidative stress

Jones¹

2008

American Journal of Physiology-Cell Physiology

1,019

839

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Free radical-induced macromolecular damage has been studied extensively as a mechanism of oxidative stress, but large-scale intervention trials with free radical scavenging antioxidant supplements show little benefit in humans. The present review summarizes data supporting a complementary hypothesis for oxidative stress in disease that can occur without free radicals. This hypothesis, which is termed the "redox hypothesis," is that oxidative stress occurs as a consequence of disruption of thiol redox circuits, which normally function in cell signaling and physiological regulation. The redox states of thiol systems are sensitive to twoelectron oxidants and controlled by the thioredoxins (Trx), glutathione (GSH), and cysteine (Cys). Trx and GSH systems are maintained under stable, but nonequilibrium conditions, due to a continuous oxidation of cell thiols at a rate of about 0.5% of the total thiol pool per minute. Redox-sensitive thiols are critical for signal transduction (e.g., H-Ras, PTP-1B), transcription factor binding to DNA (e.g., Nrf-2, nuclear factor-B), receptor activation (e.g., ␣IIb␤3 integrin in platelet activation), and other processes. Nonradical oxidants, including peroxides, aldehydes, quinones, and epoxides, are generated enzymatically from both endogenous and exogenous precursors and do not require free radicals as intermediates to oxidize or modify these thiols. Because of the nonequilibrium conditions in the thiol pathways, aberrant generation of nonradical oxidants at rates comparable to normal oxidation may be sufficient to disrupt function. Considerable opportunity exists to elucidate specific thiol control pathways and develop interventional strategies to restore normal redox control and protect against oxidative stress in aging and age-related disease.thioredoxin; glutathione; cysteine; hydrogen peroxide; redox signaling; protein thiol ONE OF THE GREAT REDOX BIOLOGISTS of the past century, Howard S. Mason, professed that to advance science, a scientist must interpret observations at the limit of their meaning. The present review of the redox biology of thiol systems addresses the possibility that disruption of the function and homeostasis of thiol systems is the most central feature of oxidative stress that contributes to mechanisms of aging and age-related disease. I have termed this the "redox hypothesis" to facilitate distinction from free radical hypotheses.Many proteins contain redox-sensitive thiols, and reactions of thiol systems occur largely by nonradical two-electron transfers. Accumulating data show that central thiol-disulfide couples are maintained under nonequilibrium conditions in biological systems. This presents a condition wherein changes in abundance and distribution of redox catalysts and changes in rates of generation of relevant oxidants (e.g., peroxides) and precursors for NADPH supply can account for pathological effects of oxidative stress through altered functions of enzymes, receptors, transporters, transcription factors, and structural elements, without free ra...

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“…7 These enzymes include GPxs, part of a family of selenium-dependent enzymes. 6,27,28 In the absence of GPx activity, subcellular concentrations of H 2 O 2 rise. Similar to the SODs, there are multiple isoforms of GPxs.…”

Section: Genetic Deficiency In Gpx1 Produces Endothelial Dysfunctionmentioning

confidence: 99%

Glutathione Peroxidase-1 Plays a Major Role in Protecting Against Angiotensin II–Induced Vascular Dysfunction

et al. 2008

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Abstract-Levels of reactive oxygen species, including hydrogen peroxide , increase in blood vessels during hypertension and in response to angiotensin II (Ang II). Although glutathione peroxidases are known to metabolize hydrogen peroxide, the role of glutathione peroxidase during hypertension is poorly defined. We tested the hypothesis that glutathione peroxidase-1 protects against Ang II-induced endothelial dysfunction. Responses of carotid arteries from Gpx1-deficient (Gpx1 ϩ/Ϫ and Gpx1 Ϫ/Ϫ ) and Gpx1 transgenic mice, and their respective littermate controls, were examined in vitro after overnight incubation with either vehicle or Ang II. Under control conditions, relaxation to acetylcholine (ACh; an endothelium-dependent agonist) was similar in control, Gpx1 ϩ/Ϫ , and Gpx1 transgenic mice, whereas in Gpx1 Ϫ/Ϫ mice, responses to ACh were impaired. In control mice, ACh-induced vasorelaxation was not affected by 1 nmol/L of Ang II. In contrast, relaxation to ACh in arteries from Gpx1 ϩ/Ϫ mice was inhibited by Ϸ60% after treatment with 1 nmol/L of Ang II, indicating that Gpx1 haploinsufficiency markedly enhances Ang II-induced endothelial dysfunction. A higher concentration of Ang II (10 nmol/L) selectively impaired relaxation to ACh in arteries from control mice, and this effect was prevented in arteries from Gpx1 transgenic mice or in arteries from control mice treated with polyethylene glycol-catalase (which degrades hydrogen peroxide). Thus, genetic and pharmacological evidence suggests a major role for glutathione peroxidase-1 and hydrogen peroxide in Ang II-induced effects on vascular function. (Hypertension. 2008;51:872-877.)

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An imbalance in antioxidant defense affects cellular function: the pathophysiological consequences of a reduction in antioxidant defense in the glutathione peroxidase-1 (Gpx1) knockout mouse

Cited by 82 publications

References 81 publications

Lack of the antioxidant glutathione peroxidase-1 does not increase atherosclerosis in C57BL/J6 mice fed a high-fat diet

Lack of the antioxidant glutathione peroxidase-1 does not increase atherosclerosis in C57BL/J6 mice fed a high-fat diet

Radical-free biology of oxidative stress

Glutathione Peroxidase-1 Plays a Major Role in Protecting Against Angiotensin II–Induced Vascular Dysfunction

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