bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2019–12–08
six papers selected by
Laia Caja Puigsubira, Uppsala University
  1. NADPH oxidase 4 mediates the protective effects of physical activity against obesity-induced vascular dysfunction.
  2. 7-Keto-Cholesterol and Cholestan-3beta, 5alpha, 6beta-Triol Induce Eryptosis through Distinct Pathways Leading to NADPH Oxidase and Nitric Oxide Synthase Activation.
  3. Attenuation of Angiotensin II-Induced Hypertension in BubR1 Low-Expression Mice Via Repression of Angiotensin II Receptor 1 Overexpression.
  4. The pentose phosphate pathway regulates chronic neuroinflammation and dopaminergic neurodegeneration.
  5. Carbon monoxide inhibits T-cell proliferation by suppressing reactive oxygen species signaling.
  6. Copper-dependent ATP7B upregulation drives the resistance of TMEM16A-overexpressing head-and-neck cancer models to platinum toxicity.
  1. Cardiovasc Res. 2019 Dec 04. pii: cvz322. [Epub ahead of print]
    NADPH oxidase 4 mediates the protective effects of physical activity against obesity-induced vascular dysfunction.
    Heike Langbein, Amna Shahid, Anja Hofmann, Jennifer Mittag, Stefan R Bornstein, Henning Morawietz, Coy Brunssen.
       AIMS: Physical activity is one of the most potent strategies to prevent endothelial dysfunction. Recent evidence suggests vaso-protective properties of H2O2 produced by main endothelial NADPH oxidase isoform 4 (Nox4) in the vasculature. Therefore, we hypothesized that Nox4 connects physical activity with vaso-protective effects.
    METHODS AND RESULTS: Analysis of the endothelial function using Mulvany Myograph showed endothelial dysfunction in wild-type as well as in Nox4-/- mice after 20 weeks on high-fat diet. Access to running wheels during the high-fat diet prevented endothelial dysfunction in wild-type but not in Nox4-/- mice. Mechanistically, exercise led to an increased H2O2 release in the aorta of wild-type mice with increased phosphorylation of eNOS pathway member AKT serine/threonine kinase 1 (AKT1). Both H2O2 release and phosphorylation of AKT1 were diminished in aortas of Nox4-/- mice. Deletion of Nox4 also resulted in lower intracellular calcium release proven by reduced phenylephrine-mediated contraction, whilst potassium-induced contraction was not affected. H2O2 scavenger catalase reduced phenylephrine-induced contraction in wild-type mice. Supplementing H2O2 increased phenylephrine-induced contraction in Nox4-/- mice.Exercise induced peroxisome proliferative activated receptor gamma, coactivator 1 alpha (Ppargc1a), as key regulator of mitochondria biogenesis in wild-type but not Nox4-/- mice. Furthermore, exercise-induced citrate synthase activity and mitochondria mass were reduced in the absence of Nox4. Thus, Nox4-/- mice became less active and ran less compared with wild-type mice.
    CONCLUSIONS: Nox4 derived H2O2 plays a key role in exercise-induced adaptations of eNOS and Ppargc1a pathway and intracellular calcium release. Hence, loss of Nox4 diminished physical activity performance and vascular protective effects of exercise.
    TRANSLATIONAL PERSPECTIVE: Reactive oxygen species are generally regarded as harmful. However, we demonstrated that Nox4, one of the main sources for reactive oxygen species is essential for exercise-mediated adaptations in the vasculature and the skeletal muscle. Hence, testing the safety and efficacy of Nox4 inhibitors in treating fibrotic disease, for example, should include cardiovascular endpoints to rule out side-effects.
    Keywords:   Nox4 ; NADPH oxidase 4; endothelial function; exercise; vascular function; voluntary running
    DOI:  https://doi.org/10.1093/cvr/cvz322
  2. Cell Physiol Biochem. 2019 ;53(6): 933-947
    7-Keto-Cholesterol and Cholestan-3beta, 5alpha, 6beta-Triol Induce Eryptosis through Distinct Pathways Leading to NADPH Oxidase and Nitric Oxide Synthase Activation.
    Alessandro Attanzio, Anna Frazzitta, Antonio Cilla, Maria A Livrea, Luisa Tesoriere, Mario Allegra.
       BACKGROUND/AIMS: We showed that patho-physiological concentrations of either 7-keto-cholesterol (7-KC), or cholestane-3beta, 5alpha, 6beta-triol (TRIOL) caused the eryptotic death of human red blood cells (RBC), strictly dependent on the early production of reactive oxygen species (ROS). The goal of the current study was to assess the contribution of the erythrocyte ROS-generating enzymes, NADPH oxidase (RBC-NOX), nitric oxide synthase (RBC-NOS) and xanthine oxido-reductase (XOR) to the oxysterol-dependent eryptosis and pertinent activation pathways.
    METHODS: Phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, reactive oxygen/nitrogen species (RONS) and nitric oxide formation from 2',7'-dichloro-dihydrofluorescein (DCF-DA) and 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate (DAF-FM DA) -dependent fluorescence, respectively; Akt1, phospho-NOS3 Ser1177, and PKCζ from Western blot analysis. The activity of individual 7-KC (7 μM) and TRIOL (2, μM) on ROS-generating enzymes and relevant activation pathways was assayed in the presence of Diphenylene iodonium chloride (DPI), N-nitro-L-arginine methyl ester (L-NAME), allopurinol, NSC23766 and LY294002, inhibitors in this order of RBC-NOX, RBC-NOS, XOR and upstream regulatory proteins Rac GTPase and phosphoinositide3 Kinase (PI3K); hemoglobin oxidation from spectrophotometric analysis.
    RESULTS: RBC-NOX was the target of 7-KC, through a signaling including Rac GTPase and PKCζ, whereas TRIOL caused activation of RBC-NOS according to the pathway PI3K/Akt, with the concurrent activity of a Rac-GTPase. In concomitance with the TRIOL-induced .NO production, formation of methemoglobin with global loss of heme were observed, ascribable to nitrosative stress. XOR, activated after modification of the redox environment by either RBC-NOX or RBC-NOS activity, concurred to the overall oxidative/nitrosative stress by either oxysterols. When 7-KC and TRIOL were combined, they acted independently and their effect on ROS/RONS production and PS exposure appeared the result of the effects of the oxysterols on RBC-NOX and RBC-NOS.
    CONCLUSION: Eryptosis of human RBCs may be caused by either 7-KC or TRIOL by oxidative/nitrosative stress through distinct signaling cascades activating RBC-NOX and RBC-NOS, respectively, with the complementary activity of XOR; when combined, the oxysterols act independently and both concur to the final eryptotic effect.
    Keywords:  Toxic oxysterols; Nitrosative stress; RBC-NOX activation; RBC-NOS activation; Eryptosis
    DOI:  https://doi.org/10.33594/000000186
  3. J Am Heart Assoc. 2019 Dec 03. 8(23): e011911
    Attenuation of Angiotensin II-Induced Hypertension in BubR1 Low-Expression Mice Via Repression of Angiotensin II Receptor 1 Overexpression.
    Yukihiko Aoyagi, Tadashi Furuyama, Kentaro Inoue, Daisuke Matsuda, Yutaka Matsubara, Arihide Okahara, Tetsuro Ago, Yutaka Nakashima, Masaki Mori, Takuya Matsumoto.
      Background Angiotensin II (Ang II) can cause hypertension and tissue impairment via AGTR1 (Ang II receptor type 1), particularly in renal proximal tubule cells, and can cause DNA damage in renal cells via nicotinamide adenine dinucleotide phosphate oxidase. BubR1 (budding uninhibited by benzimidazole-related 1) is a multifaceted kinase that functions as a mitotic checkpoint. BubR1 expression can be induced by Ang II in smooth muscle cells in vitro, but the relationship between systemic BubR1 expression and the Ang II response is unclear. Methods and Results Twenty 24-week-old male BubR1 low-expression mice (BubR1L/L mice) and age-matched BubR1+/+ mice were used in this study. We investigated how Ang II stimulation affects BubR1L/L mice. The elevated systolic blood pressure caused by Ang II stimulation in BubR1+/+ mice was significantly attenuated in BubR1L/L mice. Additionally, an attenuated level of Ang II-induced perivascular fibrosis was observed in the kidneys of BubR1L/L mice. Immunohistochemistry revealed that the overexpression of AGTR1 induced by Ang II stimulation was repressed in BubR1L/L mice. We evaluated AGTR1 and Nox-4 (nicotinamide adenine dinucleotide phosphate oxidase-4) levels to determine the role of BubR1 in the Ang II response. Results from in vitro assays of renal proximal tubule cells suggest that treatment with small interfering RNA targeting BubR1 suppressed Ang II-induced overexpression of AGTR1. Similarly, the upregulation in Nox4 and Jun N-terminal kinase induced by Ang II administration was repressed by treatment with small interfering RNA targeting BubR1. Conclusions Ang II-induced hypertension is caused by AGTR1 overexpression in the kidneys via the upregulation of BubR1 and Nox4.
    Keywords:  angiotensin II type 1 receptor; budding uninhibited by benzimidazole‐related 1; hypertension; nicotinamide adenine dinucleotide phosphate oxidase‐4; renal proximal tubule cell
    DOI:  https://doi.org/10.1161/JAHA.118.011911
  4. J Neuroinflammation. 2019 Dec 05. 16(1): 255
    The pentose phosphate pathway regulates chronic neuroinflammation and dopaminergic neurodegeneration.
    Dezhen Tu, Yun Gao, Ru Yang, Tian Guan, Jau-Shyong Hong, Hui-Ming Gao.
       BACKGROUND: Metabolic dysfunction and neuroinflammation are increasingly implicated in Parkinson's disease (PD). The pentose phosphate pathway (PPP, a metabolic pathway parallel to glycolysis) converts glucose-6-phosphate into pentoses and generates ribose-5-phosphate and NADPH thereby governing anabolic biosynthesis and redox homeostasis. Brains and immune cells display high activity of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP. A postmortem study reveals dysregulation of G6PD enzyme in brains of PD patients. However, spatial and temporal changes in activity/expression of G6PD in PD remain undetermined. More importantly, it is unclear how dysfunction of G6PD and the PPP affects neuroinflammation and neurodegeneration in PD.
    METHODS: We examined expression/activity of G6PD and its association with microglial activation and dopaminergic neurodegeneration in multiple chronic PD models generated by an intranigral/intraperitoneal injection of LPS, daily subcutaneous injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 6 days, or transgenic expression of A53T α-synuclein. Primary microglia were transfected with G6PD siRNAs and treated with lipopolysaccharide (LPS) to examine effects of G6PD knockdown on microglial activation and death of co-cultured neurons. LPS alone or with G6PD inhibitor(s) was administrated to mouse substantia nigra or midbrain neuron-glia cultures. While histological and biochemical analyses were conducted to examine microglial activation and dopaminergic neurodegeneration in vitro and in vivo, rotarod behavior test was performed to evaluate locomotor impairment in mice.
    RESULTS: Expression and activity of G6PD were elevated in LPS-treated midbrain neuron-glia cultures (an in vitro PD model) and the substantia nigra of four in vivo PD models. Such elevation was positively associated with microglial activation and dopaminergic neurodegeneration. Furthermore, inhibition of G6PD by 6-aminonicotinamide and dehydroepiandrosterone and knockdown of microglial G6PD attenuated LPS-elicited chronic dopaminergic neurodegeneration. Mechanistically, microglia with elevated G6PD activity/expression produced excessive NADPH and provided abundant substrate to over-activated NADPH oxidase (NOX2) leading to production of excessive reactive oxygen species (ROS). Knockdown and inhibition of G6PD ameliorated LPS-triggered production of ROS and activation of NF-кB thereby dampening microglial activation.
    CONCLUSIONS: Our findings indicated that G6PD-mediated PPP dysfunction and neuroinflammation exacerbated each other mediating chronic dopaminergic neurodegeneration and locomotor impairment. Insight into metabolic-inflammatory interface suggests that G6PD and NOX2 are potential therapeutic targets for PD.
    Keywords:  Glucose-6-phosphate dehydrogenase; Metabolic disruption; Microglia; NADPH oxidase; Neurodegeneration; Neuroinflammation; Oxidative stress; Pentose phosphate pathway
    DOI:  https://doi.org/10.1186/s12974-019-1659-1
  5. Antioxid Redox Signal. 2019 Dec 06.
    Carbon monoxide inhibits T-cell proliferation by suppressing reactive oxygen species signaling.
    Gang Chen, Yutao Yan, Lu Wang, Song Chen, Guangyuan Zhao, Cheng Fu, Bingyang Xu, Xiaosheng Tan, Ying Xiang.
      Aims：Carbon monoxide (CO) confers anti-proliferative effects on T cells; however, how these effects are produced remains unclear. Reactive oxygen species (ROS) have recently emerged as important modulators of T-cell proliferation. In this study, we aimed to determine whether the inhibitory effects of CO on T-cell proliferation are dependent on the inhibition of ROS signaling.
    RESULTS: Pretreatment with CO-releasing molecule-2 (CORM-2) had potent inhibitory effects on mouse T-cell proliferation stimulated by anti-CD3/CD28 antibodies. Interestingly, CORM-2 pretreatment markedly suppressed intracellular ROS generation as well as the activity of NADPH oxidase and mitochondrial complexes I-IV in T cells after stimulation. The inhibitory effects of CORM-2 on both ROS production and T-cell proliferation were comparable to those produced by the use of antioxidant NAC or a combined administration of mitochondrial complex I-IV inhibitors. Moreover, increasing intracellular ROS via H2O2 supplementation largely reversed the inhibitory effect of CORM-2 on the proliferation of T cells. The inhibitory effects of CORM-2 on both cell proliferation and intracellular ROS production were also shown in a T-cell proliferation model involving stimulation by allogeneic dendritic cells or PMA/ionomycin, as well as in spontaneous cell proliferation models in EL-4 and RAW 264.7 cells. In addition, CORM-2 treatment significantly inhibited T-cell activation in vivo and attenuated concanavalin A-induced autoimmune hepatitis.
    INNOVATION: CO inhibits T-cell proliferation via suppression of intracellular ROS production.
    CONCLUSION: The study could supply a general mechanism to explain the inhibitory effects of CO on T-cell activation and proliferation, favoring its future application in T cell-mediated diseases.
    DOI:  https://doi.org/10.1089/ars.2019.7814
  6. Biochem J. 2019 Dec 02. pii: BCJ20190591. [Epub ahead of print]
    Copper-dependent ATP7B upregulation drives the resistance of TMEM16A-overexpressing head-and-neck cancer models to platinum toxicity.
    Avani Vyas, Umamaheswar Duvvuri, Kirill Kiselyov.
      Platinum-containing drugs such as cisplatin and carboplatin are routinely used for the treatment of many solid tumors including squamous cell carcinoma of the head and neck (SCCHN). However, SCCHN resistance to platinum compounds is well documented. The resistance to platinum has been linked to the activity of divalent transporter ATP7B, which pumps platinum from the cytoplasm into lysosomes, decreasing its concentration in the cytoplasm. Several cancer models show increased expression of ATP7B; however, the reason for such an increase is not known. Here we show a strong positive correlation between mRNA levels of TMEM16A and ATP7B in human SCCHN tumors. TMEM16A overexpression and depletion in SCCHN cell lines caused parallel changes in the ATP7B mRNA levels. The ATP7B increase in TMEM16A-overexpressing cells was reversed by suppression of NADPH oxidase 2 (NOX2), by the antioxidant N-Acetyl-Cysteine (NAC) and by copper chelation using cuprizone and bathocuproine sulphonate (BCS). Pretreatment with either chelator significantly increased cisplatin's sensitivity, particularly in the context of TMEM16A overexpression. We propose that increased oxidative stress in TMEM16A-overexpressing cells liberates the chelated copper in the cytoplasm, leading to the transcriptional activation of ATP7B expression. This, in turn, decreases the efficacy of platinum compounds by promoting their vesicular sequestration. We think that such a new explanation of the mechanism of SCCHN tumors' platinum resistance identifies novel approach to treating these tumors.
    Keywords:  ATP7B; Cisplatin; TMEM16A; copper; oxidative stress
    DOI:  https://doi.org/10.1042/BCJ20190591
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