bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2020‒07‒26
four papers selected by
Laia Caja Puigsubira
Uppsala University

  1. Mol Med Rep. 2020 Sep;22(3): 2415-2423
    Mao L, Zuo ML, Wang AP, Tian Y, Dong LC, Li TM, Kuang DB, Song GL, Yang ZB.
      NADPH oxidase 2 (NOX2) is a major subtype of NOX and is responsible for the generation of reactive oxygen species (ROS) in brain tissues. MicroRNAs (miRNAs/miRs) are important epigenetic regulators of NOX2. The present study aimed to identify the role of NOX2 miRNA‑targets in ischemic stroke (IS). A rat cerebral ischemia/reperfusion (CI/R) injury model and a SH‑SY5Y cell hypoxia/reoxygenation (H/R) model were used to simulate IS. Gene expression levels, ROS production and apoptosis in tissue or cells were determined, and bioinformatic analysis was conducted for target prediction of miRNA. In vitro experiments, including function‑gain and luciferase activity assays, were also performed to assess the roles of miRNAs. The results indicated that NOX2 was significantly increased in brain tissues subjected to I/R and in SH‑SY5Y cells subjected to H/R, while the expression of miR‑532‑3p (putative target of NOX2) was significantly decreased in brain tissues and plasma. Overexpression of miR‑532‑3p significantly suppressed NOX2 expression and ROS generation in SH‑SY5Y cells subjected to H/R, as well as reduced the relative luciferase activity of cells transfected with a reporter gene plasmid. Collectively, these data indicated that miR‑532‑3p may be a target of NOX2 and a biomarker for CI/R injury. Thus, the present study may provide a novel target for drug development and IS therapy.
  2. Nat Metab. 2020 Jun;2(6): 532-546
    Seimetz M, Sommer N, Bednorz M, Pak O, Veith C, Hadzic S, Gredic M, Parajuli N, Kojonazarov B, Kraut S, Wilhelm J, Knoepp F, Henneke I, Pichl A, Kanbagli ZI, Scheibe S, Fysikopoulos A, Wu CY, Klepetko W, Jaksch P, Eichstaedt C, Grünig E, Hinderhofer K, Geiszt M, Müller N, Rezende F, Buchmann G, Wittig I, Hecker M, Hecker A, Padberg W, Dorfmüller P, Gattenlöhner S, Vogelmeier CF, Günther A, Karnati S, Baumgart-Vogt E, Schermuly RT, Ghofrani HA, Seeger W, Schröder K, Grimminger F, Brandes RP, Weissmann N.
      Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and death worldwide. Peroxynitrite, formed from nitric oxide, which is derived from inducible nitric oxide synthase, and superoxide, has been implicated in the development of emphysema, but the source of the superoxide was hitherto not characterized. Here, we identify the non-phagocytic NADPH oxidase organizer 1 (NOXO1) as the superoxide source and an essential driver of smoke-induced emphysema and pulmonary hypertension development in mice. NOXO1 is consistently upregulated in two models of lung emphysema, Cybb (also known as NADPH oxidase 2, Nox2)-knockout mice and wild-type mice with tobacco-smoke-induced emphysema, and in human COPD. Noxo1-knockout mice are protected against tobacco-smoke-induced pulmonary hypertension and emphysema. Quantification of superoxide, nitrotyrosine and multiple NOXO1-dependent signalling pathways confirm that peroxynitrite formation from nitric oxide and superoxide is a driver of lung emphysema. Our results suggest that NOXO1 may have potential as a therapeutic target in emphysema.
  3. Hypertension. 2020 Jul 20. HYPERTENSIONAHA12015558
    Zhao GJ, Zhao CL, Ouyang S, Deng KQ, Zhu L, Montezano AC, Zhang C, Hu F, Zhu XY, Tian S, Liu X, Ji YX, Zhang P, Zhang XJ, She ZG, Touyz RM, Li H.
      NOX5 (NADPH oxidase 5) is a homolog of the gp91phox subunit of the phagocyte NOX, which generates reactive oxygen species. NOX5 is involved in sperm motility and vascular contraction and has been implicated in diabetic nephropathy, atherosclerosis, and stroke. The function of NOX5 in the cardiac hypertrophy is unknown. Because NOX5 is a Ca2+-sensitive, procontractile NOX isoform, we questioned whether it plays a role in cardiac hypertrophy. Studies were performed in (1) cardiac tissue from patients undergoing heart transplant for cardiomyopathy and heart failure, (2) NOX5-expressing rat cardiomyocytes, and (3) mice expressing human NOX5 in a cardiomyocyte-specific manner. Cardiac hypertrophy was induced in mice by transverse aorta coarctation and Ang II (angiotensin II) infusion. NOX5 expression was increased in human failing hearts. Rat cardiomyocytes infected with adenoviral vector encoding human NOX5 cDNA exhibited elevated reactive oxygen species levels with significant enlargement and associated increased expression of ANP (atrial natriuretic peptides) and β-MHC (β-myosin heavy chain) and prohypertrophic genes (Nppa, Nppb, and Myh7) under Ang II stimulation. These effects were reduced by N-acetylcysteine and diltiazem. Pressure overload and Ang II infusion induced left ventricular hypertrophy, interstitial fibrosis, and contractile dysfunction, responses that were exaggerated in cardiac-specific NOX5 trangenic mice. These phenomena were associated with increased reactive oxygen species levels and activation of redox-sensitive MAPK (mitogen-activated protein kinase). N-acetylcysteine treatment reduced cardiac oxidative stress and attenuated cardiac hypertrophy in NOX5 trangenic. Our study defines Ca2+-regulated NOX5 as an important NOX isoform involved in oxidative stress- and MAPK-mediated cardiac hypertrophy and contractile dysfunction.
    Keywords:  NADPH oxidase; calcium; heart failure; hypertrophy; reactive oxidative species
  4. Nat Metab. 2019 Mar;1(3): 404-415
    Chen L, Zhang Z, Hoshino A, Zheng HD, Morley M, Arany Z, Rabinowitz JD.
      NADPH donates high-energy electrons for antioxidant defence and reductive biosynthesis. Cytosolic NADP is recycled to NADPH by the oxidative pentose-phosphate pathway (oxPPP), malic enzyme 1 (ME1) and isocitrate dehydrogenase 1 (IDH1). Here we show that any one of these routes can support cell growth, but the oxPPP is uniquely required to maintain a normal NADPH/NADP ratio, mammalian dihydrofolate reductase (DHFR) activity and folate metabolism. These findings are based on CRISPR deletions of glucose-6-phosphate dehydrogenase (G6PD, the committed oxPPP enzyme), ME1, IDH1 and combinations thereof in HCT116 colon cancer cells. Loss of G6PD results in high NADP, which induces compensatory increases in ME1 and IDH1 flux. But the high NADP inhibits DHFR, resulting in impaired folate-mediated biosynthesis, which is reversed by recombinant expression of Escherichia coli DHFR. Across different cancer cell lines, G6PD deletion produced consistent changes in folate-related metabolites, suggesting a general requirement for the oxPPP to support folate metabolism.