bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2019‒10‒06
four papers selected by
Laia Caja Puigsubira
Uppsala University

  1. Redox Biol. 2019 Sep 20. pii: S2213-2317(19)30803-1. [Epub ahead of print]28 101330
    Muñoz M, López-Oliva ME, Rodríguez C, Martínez MP, Sáenz-Medina J, Sánchez A, Climent B, Benedito S, García-Sacristán A, Rivera L, Hernández M, Prieto D.
      Oxidative stress-associated endothelial dysfunction is a key pathogenic factor underlying the microvascular complications of metabolic disease. NADPH oxidase (Nox) is a major source of oxidative stress in diabetic nephropathy and chronic kidney disease, despite Nox4 and Nox2 have been identified as relevant sources of vasodilator endothelial H2O2.The present study was sought to investigate the role of Nox enzymes in renal vascular oxidative stress and endothelial dysfunction in a rat model of genetic obesity. Endothelial function was assessed in intrarenal arteries of obese Zucker rats (OZR) and their counterparts lean Zucker rats (LZR) mounted in microvascular myographs, and superoxide (O2.-) and H2O2 production were measured. Impaired endothelium-dependent relaxations to acetylcholine (ACh) were associated to augmented O2.- generation, but neither ROS scavengers nor the Nox inhibitor apocynin significantly improved these relaxant responses in renal arteries of OZR. Whereas NO contribution to endothelial relaxations was blunted, catalase-sensitive non-NO non-prostanoid relaxations were enhanced in obese rats. Interestingly, NADPH-dependent O2.- production was augmented while NADPH-dependent H2O2 generation was reduced, and cytosolic and mitochondrial SOD were up-regulated in kidney of obese rats. Nox4 was down-regulated in renal arteries and Nox4-dependent H2O2 generation and endothelial relaxation were reduced in OZR. Up-regulation of both Nox2 and Nox1 was associated with augmented O2.- production but reduced H2O2 generation and blunted endothelial Nox2-derived H2O2-mediated in obese rats. Moreover, increased Nox1-derived O2.- contributed to renal endothelial dysfunction in OZR. In summary, the current data support a main role for Nox1-derived O2.- in kidney vascular oxidative stress and renal endothelial dysfunction in obesity, while reduced endothelial Nox4 expression associated to decreased H2O2 generation and H2O2-mediated vasodilatation might hinder Nox4 protective renal effects thus contributing to kidney injury. This suggests that effective therapies to counteract oxidative stress and prevent microvascular complications must identify the specific Nox subunits involved in metabolic disease.
    Keywords:  Endothelial dysfunction; Nox1; Nox2; Nox4; Obesity; Oxidative stress; Renal arteries
  2. Free Radic Biol Med. 2019 Oct 01. pii: S0891-5849(19)31083-4. [Epub ahead of print]
    Knock G.
      The last 20-25 years have seen an explosion of interest in the role of NADPH oxidase (NOX) in cardiovascular function and disease. In vascular smooth muscle and endothelium, NOX generates reactive oxygen species (ROS) that act as second messengers, contributing to the control of normal vascular function. NOX activity is altered in response to a variety of stimuli, including G-protein coupled receptor agonists, growth-factors, perfusion pressure, flow and hypoxia. NOX-derived ROS are involved in smooth muscle constriction, endothelium-dependent relaxation and smooth muscle growth, proliferation and migration, thus contributing to the fine-tuning of blood flow, arterial wall thickness and vascular resistance. Through reversible oxidative modification of target proteins, ROS regulate the activity of protein tyrosine phosphatases, kinases, G proteins, ion channels, cytoskeletal proteins and transcription factors. There is now considerable, but somewhat contradictory evidence that NOX contributes to the pathogenesis of hypertension through oxidative stress. Specific NOX isoforms have been implicated in endothelial dysfunction, hyper-contractility and vascular remodelling in various animal models of hypertension, pulmonary hypertension and pulmonary arterial hypertension, but also have potential protective effects, particularly NOX4. This review explores the multiplicity of NOX function in the healthy vasculature and the evidence for and against targeting NOX for antihypertensive therapy.
  3. Int J Mol Cell Med. 2018 ;7(3): 193-202
    Yahyapour R, Amini P, Saffar H, Rezapoor S, Motevaseli E, Cheki M, Farhood B, Nouruzi F, Shabeeb D, Eleojo Musa A, Najafi M.
      Radiation-induced heart toxicity is one of the serious side effects after a radiation disaster or radiotherapy for patients with chest cancers, leading to a reduction in the quality of life of the patients. Evidence has shown that infiltration of inflammatory cells plays a key role in the development of functional damages to the heart via chronic upregulation of some pro-fibrotic and pro-inflammatory cytokines. These changes are associated with continuous free radical production and increased stiffness of heart muscle. IL-4 and IL-13 are two important pro-fibrotic cytokines which contribute to the side effects of ionizing radiation exposure. Recent studies have proposed that IL-4 through upregulation of DUOX2, and IL-13 via stimulation of DUOX1 gene expression, are involved in the development of radiation late effects. In the present study, we aimed to detect changes in the expression of these pathways following irradiation of rat's heart. Furthermore, we evaluated the possible protective effect of metformin on the development of these abnormal changes. 20 male rats were divided into 4 groups (control, radiation, metformin treated, metformin + radiation). These rats were irradiated with 15 Gy 60Co gamma rays, and sacrificed after 10 weeks for evaluation of the changes in the expression of IL4R1, IL-13R2a, DUOX1 and DUOX2. In addition, the levels of IL-4 and IL-13 cytokines, as well as infiltration of macrophages and lymphocytes were detected. Results showed an upregulation of both DUOX1 and DUOX2 pathways in the presence of metformin, while the level of IL-13 did not show any significant change. This was associated with infiltration of macrophages and lymphocytes. Also, treatment with metformin could significantly attenuate accumulation of inflammatory cells, and upregulate these pathways. Therefore, suppression of dual oxidase genes by metformin may be a contributory factor to its protective effect.
    Keywords:  DUOX2; Heart Injury; IL-13; DUOX1; IL-4; Metformin; Radiation
  4. Oxid Med Cell Longev. 2019 ;2019 3201062
    Vlad ML, Manea SA, Lazar AG, Raicu M, Muresian H, Simionescu M, Manea A.
      Histone acetylation plays a major role in epigenetic regulation of gene expression. Monocyte-derived macrophages express functional NADPH oxidase 5 (Nox5) that contributes to oxidative stress in atherogenesis. The mechanisms of Nox5 regulation are not entirely elucidated. The aim of this study was to investigate the expression pattern of key histone acetyltransferase subtypes (p300, HAT1) in human atherosclerosis and to determine their role in mediating the upregulation of Nox5 in macrophages under inflammatory conditions. Human nonatherosclerotic and atherosclerotic tissue samples were collected in order to determine the expression of p300 and HAT1 isoforms, H3K27ac, and Nox5. In vitro determinations were done on human macrophages exposed to lipopolysaccharide in the absence or presence of histone acetyltransferase inhibitors. Western blot, immunohistochemistry, immunofluorescence, real-time PCR, transfection, and chromatin immunoprecipitation assay were employed. The protein levels of p300 and HAT1 isoforms, H3K27ac, and Nox5 were found significantly elevated in human atherosclerotic specimens. Immunohistochemistry/immunofluorescence staining revealed that p300, HAT1, H3K27ac, H3K9ac, and Nox5 proteins were colocalized in the area of CD45+/CD68+ immune cells and lipid-rich deposits within human atherosclerotic plaques. Lipopolysaccharide induced the levels of HAT1, H3K27ac, H3K9ac, and Nox5 and the recruitment of p300 and HAT1 at the sites of active transcription within Nox5 gene promoter in cultured human macrophages. Pharmacological inhibition of histone acetyltransferase significantly reduced the Nox5 gene and protein expression in lipopolysaccharide-challenged macrophages. The overexpression of p300 or HAT1 enhanced the Nox5 gene promoter activity. The histone acetyltransferase system is altered in human atherosclerosis. Under inflammatory conditions, HAT subtypes control Nox5 overexpression in cultured human macrophages. The data suggest the existence of a new epigenetic mechanism underlying oxidative stress in atherosclerosis.