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Abstract: Enforced expression of GNG11, G-protein subunit [gamma] 11, induces cellular senescence in normal human diploid fibroblasts. We here examined the effect of the expression of GNG11 on the growth [...]

NADPH oxidase (NOX) is a major source of reactive oxygen species (ROS) in the body and it plays a key role in mediation of oxidative injury in the cardiovascular system. The purposes of this study are to evaluate the status of NOX in endothelial progenitor cells (EPCs) of hyperlipidemic rats and to determine whether NOX-derived ROS promotes the dysfunction of EPCs. The rats were fed on a high-fat diet for 8 weeks to establish a hyperlipidemic rat model, which showed the increased plasma lipids and the impaired functions of circulating EPCs (including the reduced abilities in migration and adhesion) accompanied by an increase in NOX activity and ROS production. Next, EPCs were isolated from normal rats and they were treated with oxidized low-density lipoprotein (ox-LDL) (100 [micro]g/mL) for 24 h to induce a dysfunctional model in vitro. In agreement with our findings in vivo, ox-LDL treatment increased the dysfunctions of EPCs concomitant with an increase in NOX activity and ROS production; these phenomena were reversed by the NOX inhibitor. Based on these observations, we conclude that NOX-derived ROS involved in the dysfunctions of circulating EPCs in hyperlipidemic rats and inhibition of NOX might provide a novel strategy to improve EPC functions in hyperlipidemia. Key words: hyperlipidemia, NADPH oxidase, endothelial progenitor cells, reactive oxygen species, oxidized low-density lipoprotein. La NADPH oxydase (NOX) est une importante source de derives reactifs de l'oxygene (ROS) dans l'organisme, qui joue un role cle dans la mediation des lesions oxydatives dans le systeme cardiovasculaire. Cette etude avait pour buts d'evaluer le statut de la NOX dans les cellules endotheliales progenitrices (CEP) de rats hyperlipidemiques et d'etablir si les ROS derives de la NOX favorisent le dysfonctionnement des CEP. Nous avons donc administre aux rats un regime haute teneur en matieres grasses pendant 8 semaines en vue d'obtenir un modele de rat hyperlipidemique, dans lequel nous avons observe une augmentation des taux plasmatiques de lipides et une deterioration du fonctionnement des CEP en circulation (y compris de la diminution des capacites de migration et d'adherence), accompagnees d'une augmentation de l'activite de la NOX et de la production de ROS. Nous avons ensuite isole des CEP de rats normaux et nous les avons exposees ;a des lipoproteines de basse densite oxydees (LDL-ox) (a 100 [micro]g/mL) pendant 24 h en vue d'obtenir un modele dysfonctionnel in vitro. En accord avec les resultats que nous avons obtenus in vivo, l'exposition aux LDL-ox a entraine une augmentation des dysfonctionnements au niveau des CEP, qui etait concomitante ;a une augmentation de l'activite de la NOX et de la production de ROS; un inhibiteur de la NOX a permis de neutraliser ces phenomenes. D'apres ces observations, nous en arrivons la conclusion qu'en jouant un role dans le dysfonctionnement des CEP en circulation chez le rat hyperlipidemique et dans l'inhibition de la NOX, les ROS derives de la NOX pourraient permettre d'obtenir une nouvelle strategie visant ;a ameliorer le fonctionnement des CEP dans un contexte d'hyperlipidemie. [Traduit par la Redaction] Mots-cles : hyperlipidemie, NADPH oxydase, cellules endotheliales progenitrices, derives reactifs de l'oxygene, lipoproteines de basse densite oxydees., Introduction It is well known that hyperlipidemia contributes greatly to atherosclerosis and atherosclerosis-associated diseases such as coronary heart disease, hypertension, and stroke. Numerous studies from animals and humans have demonstrated [...]

Oxidative damage from elevated production of reactive oxygen species (ROS) contributes to ischemia-reperfusion injury in myocardial infarction and stroke. The mechanism by which the increase in ROS occurs is not [...]

ABSTRACT Our previous study found that curcumin, a major active component of turmeric, could ameliorate ethanol-induced hepatocytes oxidative stress in vitro. The objective of this work was to investigate the [...]

Mice with a knock-in mutation (Y524S) in the type I ryanodine receptor (Ryr1), a mutation analogous to the Y522S mutation that is associated with malignant hyperthermia in humans, die when [...]

Reactive oxygen species (ROS) are mutagenic and may thereby promote cancer (1). Normally, ROS levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors and is predominantly regulated by the transcription factor Nrf2 (also known as Nfe2l2) and its repressor protein Keapl (refs 2-5). In contrast to the acute physiological regulation of Nrf2, in neoplasia there is evidence for increased basal activation of Nrf2. Indeed, somatic mutations that disrupt the Nrf2-Keap1 interaction to stabilize Nrf2 and increase the constitutive transcription of Nrf2 target genes were recently identified, indicating that enhanced ROS detoxification and additional Nrf2 functions may in fact be protumorigenic (6). Here, we investigated ROS metabolism in primary murine cells following the expression of endogenous oncogenic alleles of Kras, Braf and Myc, and found that ROS are actively suppressed by these oncogenes. [K-Ras.sup.G12D], [B-Raf.sup.V619E] and [Myc.sup.ERT2] each increased the transcription of Nrf2 to stably elevate the basal Nrf2 antioxidant program and thereby lower intracellular ROS and confer a more reduced intracellular environment. Oncogene-directed increased expression of Nrf2 is a new mechanism for the activation of the Nrf2 antioxidant program, and is evident in primary cells and tissues of mice expressing [K-Ras.sup.G12D] and [B-Raf.sup.V619E], and in human pancreatic cancer. Furthermore, genetic targeting of the Nrf2 pathway impairs [K-Ras.sup.G12D]-induced proliferation and tumorigenesis in vivo. Thus, the Nrf2 antioxidant and cellular detoxification program represents a previously unappreciated mediator of oncogenesis., To examine the role of ROS in cellular transformation and tumorigenesis, we used an endogenous and conditional oncogenic LSL-[K-Ras.sup.G12D] allele (7). [K-Ras.sup.G12D/+] and [K-Ras.sup.LSL/+] mouse embryonic fibroblasts (MEFs) were compared [...]

Abstract Reactive oxygen species (ROS) are thought to underline the process of ageing and the pathogenicity of various diseases, such as neurodegenerative disorders and cancer. The use of traditional medicine [...]

Proinflammatory stimuli induce inflammation that may progress to sepsis or chronic inflammatory disease. The cytokine TNF-αis an important endotoxin-induced inflammatory glycoprotein produced predominantly by macrophages and lymphocytes. TNF-αplays a major [...]

A unified model for the actions of classic antibiotics has been proposed through which they kill bacteria by stimulating the formation of reactive oxygen species (ROS). Despite its appeal, this [...]