NADPH & NADPH Oxidase: Functions + Health Effects

Myocardial NADPH oxidase-4 regulates the physiological response to acute exercise

NADPH & NADPH Oxidase: Functions + Health Effects

Regular exercise has widespread health benefits. Fundamental to these beneficial effects is the ability of the heart to intermittently and substantially increase its performance without incurring damage, but the underlying homeostatic mechanisms are unclear.

We identify the ROS-generating NADPH oxidase-4 (Nox4) as an essential regulator of exercise performance in mice. Myocardial Nox4 levels increase during acute exercise and trigger activation of the transcription factor Nrf2, with the induction of multiple endogenous antioxidants.

Cardiomyocyte-specific Nox4-deficient (csNox4KO) mice display a loss of exercise-induced Nrf2 activation, cardiac oxidative stress and reduced exercise performance.

Cardiomyocyte-specific Nrf2-deficient (csNrf2KO) mice exhibit similar compromised exercise capacity, with mitochondrial and cardiac dysfunction.

Supplementation with an Nrf2 activator or a mitochondria-targeted antioxidant effectively restores cardiac performance and exercise capacity in csNox4KO and csNrf2KO mice respectively. The Nox4/Nrf2 axis therefore drives a hormetic response that is required for optimal cardiac mitochondrial and contractile function during physiological exercise.

https://doi.org/10.7554/eLife.41044.001

Regular physical exercise has widespread beneficial effects on multiple body systems in healthy individuals and increases quality of life and lifespan.

It is one of the most effective ways of preventing cardiovascular disease through reduction in risk factors such as obesity, hypertension and metabolic syndrome and by enhancing vascular function (Mann and Rosenzweig, 2012).

Regular exercise also reduces morbidity and mortality in conditions such as chronic heart failure and dementia (Sharma et al., 2015).

Fundamental to these beneficial effects of exercise is the capacity of the heart to substantially increase its performance and output during exercise, safely and without detriment to the heart itself. The intrinsic mechanisms that underlie the physiological adaptation of the heart to regular exercise are therefore crucial to its overall beneficial effects (Vega et al., 2017).

Previous studies show that intrinsic pathways that mediate cardiac adaptive responses to exercise are triggered rapidly, even after just 1–3 bouts of consecutive exercise, and are sufficiently robust to provide significant cardioprotection (Demirel et al., 2001; Powers et al., 2008).

Among the candidate pathways involved in the adaptive response to acute exercise are those that maintain a balance between reactive oxygen species (ROS) and endogenous antioxidant defences.

The maintenance of a physiological redox state is crucial for all cellular functions and is ly to be especially important when cardiac workload and the activity of metabolic pathways that support it are changing rapidly during exercise. Myocardial ROS levels rise transiently during acute exercise (Muthusamy et al.

, 2012), which is thought to be related to enhanced activity of the mitochondrial respiratory chain during increases in cardiac contractility. Excessive levels of ROS (oxidative stress) could cause damage to membranes, proteins and DNA and lead to detrimental consequences such as mitochondrial, metabolic and cellular dysfunction.

However, these potentially detrimental effects are limited by endogenous antioxidant defences, and exercise has been found to increase antioxidant capacity in the heart and skeletal muscle (Powers et al., 2014; Radak et al., 2017).

Interestingly, low-level increases in ROS may themselves induce a response that counteracts oxidative stress (termed hormesis), which represents a physiological adaptive mechanism (Radak et al., 2017). However, the sources of ROS that may be involved and their regulatory roles in this process remain elusive.

Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor which is a master regulator of cellular redox balance.

It binds to antioxidant response elements (AREs) in the promoter regions of its target genes which include enzymes involved in glutathione biosynthesis and maintenance such as glutamate-cysteine ligase catalytic subunit (GCLC) and glutathione reductase; antioxidant enzymes such as catalase (CAT), thioredoxin reductases (TRXRs) and haem oxygenase-1, and detoxification enzymes such as NAD(P)H quinone dehydrogenase 1 (NQO1) and glutathione S-transferases (GSTs) (Niture et al., 2014). Nrf2 normally undergoes rapid turnover through ubiquitination and proteosomal degradation. However, upon exposure to oxidants or electrophiles, its associated protein Keap1 is modified and enables Nrf2 to be stabilised and then accumulate in the nucleus to mediate gene transcription. Previous work implicates the upregulation of Nrf2 and endogenous antioxidant defences as an adaptive response to exercise in heart and skeletal muscle (Done and Traustadóttir, 2016; Muthusamy et al., 2012; Oh et al., 2017; Wang et al., 2016).

NADPH oxidase-4 (Nox4) is a member of the Nox family proteins, which generate ROS by catalysing electron transfer from NADPH to molecular O2 (Lassègue et al., 2012).

Un other ROS sources such as mitochondria, uncoupled nitric oxide synthases and xanthine oxidases, the Nox enzymes produce ROS as their primary function and have been shown to be involved in diverse redox signalling pathways. In contrast to other mammalian Nox isoforms, Nox4 is constitutively active and is regulated mainly by its abundance (Zhang et al., 2013).

Previous studies show that cardiac Nox4 levels rise in response to diverse cellular stresses (Lassègue et al., 2012; Zhang et al., 2010), in part as a transcriptional response to ATF4 (Santos et al., 2016).

In the disease setting of chronic pressure overload, the upregulation of Nox4 promotes adaptive cardiac remodelling through effects that include a preservation of myocardial capillary density (Zhang et al., 2010; Zhang et al., 2018) and an Nrf2-dependent enhancement of myocardial redox state (Smyrnias et al., 2015). However, it is not known whether Nox4 plays any physiological role in the heart.

Here, we report that cardiomyocyte Nox4 is an essential mediator of the physiological activation of the Nrf2 pathway during acute exercise, triggering an adaptive response that preserves redox balance, mitochondrial function and exercise performance. Our findings identify a novel physiological pathway that is required for the heart to safely and efficiently support physical exercise.

It was previously shown that Nox4 mRNA and protein levels are low in the adult mouse heart but are upregulated by chronic hemodynamic overload (Zhang et al., 2010). We first analysed whether myocardial Nox4 levels change in response to physiological exercise.

In mice subjected to 2 bouts of 1500 m moderate intensity treadmill exercise on consecutive days, there was a significant increase in myocardial Nox4 mRNA and protein levels as compared to sedentary mice (Figure 1A and Figure 1—figure supplement 1A).

No change was observed in the expression levels of Nox2, the other main Nox isoform that is expressed in the heart (Figure 1—figure supplement 2A) or in Nox2 activation as assessed by the membrane translocation of its essential regulatory subunit, p47phox, after physiological exercise (Figure 1—figure supplement 2B).

We next conducted a maximal exercise capacity test in which Nox4-null mice and matched wild-type littermates were run to exhaustion on day 3.

This test revealed that Nox4-null mice had a maximal running distance that was ~60% of that in wild-type controls and a maximal running time that was ~65% of that in controls (Figure 1B). These results indicate that Nox4 has an essential role in facilitating acute exercise in healthy mice.

(A) Changes in myocardial Nox4 mRNA and protein levels after acute moderate exercise (Ex) compared to sedentary controls (Sed). *p

Source: https://elifesciences.org/articles/41044

Dual oxidase 1 and NADPH oxidase 2 exert favorable effects in cervical cancer patients by activating immune response

NADPH & NADPH Oxidase: Functions + Health Effects

  1. 1.

    McCredie MR, Sharples KJ, Paul C, Baranyai J, Medley G, Jones RW, et al. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol. 2008;9:425–34.

    • PubMed
    • Article
    • PubMed Central
    • Google Scholar
  2. 2.

    Cromme FV, Meijer CJ, Snijders PJ, Uyterlinde A, Kenemans P, Helmerhorst T, et al. Analysis of MHC class I and II expression in relation to presence of HPV genotypes in premalignant and malignant cervical lesions. Br J Cancer. 1993;67:1372–80.

    • CAS
    • PubMed
    • PubMed Central
    • Article
    • Google Scholar
  3. 3.

    Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol. 2012;23:6–9.

  4. 4.

    Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 2007;87:245–313.

    • CAS
    • PubMed
    • Article
    • PubMed Central
    • Google Scholar
  5. 5.

    Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature. 2000;408:239–47.

    • CAS
    • PubMed
    • Article
    • Google Scholar
  6. 6.

    Roy K, Wu Y, Meitzler JL, Juhasz A, Liu H, Jiang G, et al. NADPH oxidases and cancer. Clin Sci (Lond). 2015;128:863–75.

    • CAS
    • Article
    • Google Scholar
  7. 7.

    Rada B, Leto TL. Oxidative innate immune defenses by Nox/Duox family NADPH oxidases. Contrib Microbiol. 2008;15:164–87.

    • CAS
    • PubMed
    • PubMed Central
    • Article
    • Google Scholar
  8. 8.

    Bae YS, Choi MK, Lee WJ. Dual oxidase in mucosal immunity and host-microbe homeostasis. Trends Immunol. 2010;31:278–87.

    • CAS
    • PubMed
    • Article
    • Google Scholar
  9. 9.

    Geiszt M, Witta J, Baffi J, Lekstrom K, Leto TL. Dual oxidases represent novel hydrogen peroxide sources supporting mucosal surface host defense. FASEB J. 2003;17:1502–4.

    • CAS
    • PubMed
    • Article
    • Google Scholar
  10. 10.

    Edens WA, Sharling L, Cheng G, Shapira R, Kinkade JM, Lee T, et al. Tyrosine cross-linking of extracellular matrix is catalyzed by Duox, a multidomain oxidase/peroxidase with homology to the phagocyte oxidase subunit gp91phox. J Cell Biol. 2001;154:879–91.

    • CAS
    • PubMed
    • PubMed Central
    • Article
    • Google Scholar
  11. 11.

    Anh NT, Nishitani M, Harada S, Yamaguchi M, Kamei K. Essential role of Duox in stabilization of Drosophila wing. J Biol Chem. 2011;286:33244–51.

    • CAS
    • PubMed
    • PubMed Central
    • Article
    • Google Scholar
  12. 12.

    Xiao X, Yang L, Pang X, Zhang R, Zhu Y, Wang P, et al. A mesh-Duox pathway regulates homeostasis in the insect gut. Nat Microbiol. 2017;2:17020.

    • PubMed
    • PubMed Central
    • Article
    • Google Scholar
  13. 13.

    Flores MV, Crawford KC, Pullin LM, Hall CJ, Crosier KE, Crosier PS. Dual oxidase in the intestinal epithelium of zebrafish larvae has anti-bacterial properties. Biochem Biophys Res Commun. 2010;400:164–8.

    • CAS
    • PubMed
    • Article
    • PubMed Central
    • Google Scholar
  14. 14.

    Kawahara T, Quinn MT, Lambeth JD. Molecular evolution of the reactive oxygen-generating NADPH oxidase (Nox/Duox) family of enzymes. BMC Evol Biol. 2007;7:109.

    • PubMed
    • PubMed Central
    • Article
    • CAS
    • Google Scholar
  15. 15.

    Kanehisa M, Goto S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28:27–30.

    • CAS
    • PubMed
    • PubMed Central
    • Article
    • Google Scholar
  16. 16.

    Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12:453–7.

    • CAS
    • PubMed
    • PubMed Central
    • Article
    • Google Scholar
  17. 17.

    Strengert M, Jennings R, Davanture S, Hayes P, Gabriel G, Knaus UG. Mucosal reactive oxygen species are required for antiviral response: role of Duox in influenza a virus infection. Antioxid Redox Signal. 2014;20:2695–709.

    • CAS
    • PubMed
    • Article
    • Google Scholar
  18. 18.

    Dupuy C, Ohayon R, Valent A, Noel-Hudson MS, Deme D, Virion A. Purification of a novel flavoprotein involved in the thyroid NADPH oxidase. Cloning of the porcine and human cDNAs. J Biol Chem. 1999;274:37265–9.

    • CAS
    • PubMed
    • Article
    • Google Scholar
  19. 19.

    De Deken X, Wang D, Many MC, Costagliola S, Libert F, Vassart G, et al. Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family. J Biol Chem. 2000;275:23227–33.

    • PubMed
    • Article
    • Google Scholar
  20. 20.

    Degroot LJ, Niepomniszcze H. Biosynthesis of thyroid hormone: basic and clinical aspects. Metabolism. 1977;26:665–718.

    • CAS
    • PubMed
    • Article
    • Google Scholar
  21. 21.

    Ameziane-El-Hassani R, Talbot M, de Souza Dos Santos MC, Al Ghuzlan A, Hartl D, Bidart JM, et al. NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation. Proc Natl Acad Sci U S A. 2015;112:5051–6.

    • CAS
    • PubMed
    • PubMed Central
    • Article
    • Google Scholar
  22. 22.

    Ameziane-El-Hassani R, Schlumberger M, Dupuy C. NADPH oxidases: new actors in thyroid cancer? Nat Rev Endocrinol. 2016;12:485–94.

    • CAS
    • PubMed
    • Article
    • PubMed Central
    • Google Scholar
  23. 23.

    Little AC, Sulovari A, Danyal K, Heppner DE, Seward DJ, van der Vliet A. Paradoxical roles of dual oxidases in cancer biology. Free Radic Biol Med. 2017;110:117–32.

    • CAS
    • PubMed
    • PubMed Central
    • Article
    • Google Scholar
  24. 24.

    Luxen S, Belinsky SA, Knaus UG. Silencing of DUOX NADPH oxidases by promoter hypermethylation in lung cancer. Cancer Res. 2008;68:1037–45.

    • CAS
    • PubMed
    • Article
    • PubMed Central
    • Google Scholar
  25. 25.

    Little AC, Sham D, Hristova M, Danyal K, Heppner DE, Bauer RA, et al. DUOX1 silencing in lung cancer promotes EMT, cancer stem cell characteristics and invasive properties. Oncogenesis. 2016;5:e261.

    • CAS
    • PubMed
    • PubMed Central
    • Article
    • Google Scholar
  26. 26.

    Aviello G, Knaus UG. ROS in gastrointestinal inflammation: rescue or sabotage? Br J Pharmacol. 2017;174:1704–18.

    • CAS
    • PubMed
    • Article
    • Google Scholar
  27. 27.

    You X, Ma M, Hou G, Hu Y, Shi X. Gene expression and prognosis of NOX family members in gastric cancer. Onco Targets Ther. 2018;11:3065–74.

    • PubMed
    • PubMed Central
    • Article
    • Google Scholar
  28. 28.

    El Hassani RA, Benfares N, Caillou B, Talbot M, Sabourin JC, Belotte V, et al. Dual oxidase2 is expressed all along the digestive tract. Am J Physiol Gastrointest Liver Physiol. 2005;288:G933–42.

    • PubMed
    • Article
    • CAS
    • Google Scholar
  29. 29.

    MacFie TS, Poulsom R, Parker A, Warnes G, Boitsova T, Nijhuis A, et al. DUOX2 and DUOXA2 form the predominant enzyme system capable of producing the reactive oxygen species H2O2 in active ulcerative colitis and are modulated by 5-aminosalicylic acid. Inflamm Bowel Dis. 2014;20:514–24.

    • PubMed
    • Article
    • Google Scholar
  30. 30.

    Deep G, Kumar R, Jain AK, Dhar D, Panigrahi GK, Hussain A, et al. Graviola inhibits hypoxia-induced NADPH oxidase activity in prostate cancer cells reducing their proliferation and clonogenicity. Sci Rep. 2016;6:23135.

    • CAS
    • PubMed
    • PubMed Central
    • Article
    • Google Scholar
  31. 31.

    Guo Y, Han B, Luo K, Ren Z, Cai L, Sun L. NOX2-ROS-HIF-1alpha signaling is critical for the inhibitory effect of oleanolic acid on rectal cancer cell proliferation. Biomed Pharmacother. 2017;85:733–9.

    • CAS
    • PubMed
    • Article
    • PubMed Central
    • Google Scholar
  32. 32.

    Mukawera E, Chartier S, Williams V, Pagano PJ, Lapointe R, Grandvaux N. Redox-modulating agents target NOX2-dependent IKKepsilon oncogenic kinase expression and proliferation in human breast cancer cell lines. Redox Biol. 2015;6:9–18.

    • CAS
    • PubMed
    • PubMed Central
    • Article
    • Google Scholar
  33. 33.

    Parker BS, Rautela J, Hertzog PJ. Antitumour actions of interferons: implications for cancer therapy. Nat Rev Cancer. 2016;16:131–44.

    • PubMed
    • Article
    • CAS
    • PubMed Central
    • Google Scholar
  34. 34.

    Kwon J, Shatynski KE, Chen H, Morand S, de Deken X, Miot F, et al. The nonphagocytic NADPH oxidase Duox1 mediates a positive feedback loop during T cell receptor signaling. Sci Signal. 2010;3:ra59.

    • PubMed
    • PubMed Central
    • Article
    • CAS
    • Google Scholar
  35. 35.

    Rada B, Park JJ, Sil P, Geiszt M, Leto TL. NLRP3 inflammasome activation and interleukin-1beta release in macrophages require calcium but are independent of calcium-activated NADPH oxidases. Inflamm Res. 2014;63:821–30.

    • CAS
    • PubMed
    • PubMed Central
    • Article
    • Google Scholar
  36. 36.

    Habibovic A, Hristova M, Heppner DE, Danyal K, Ather JL, Janssen-Heininger YM, et al. DUOX1 mediates persistent epithelial EGFR activation, mucous cell metaplasia, and airway remodeling during allergic asthma. JCI Insight. 2016;1:e88811.

    • PubMed
    • PubMed Central
    • Article
    • Google Scholar
  37. 37.

    Deffert C, Cachat J, Krause KH. Phagocyte NADPH oxidase, chronic granulomatous disease and mycobacterial infections. Cell Microbiol. 2014;16:1168–78.

    • CAS
    • PubMed
    • Article
    • PubMed Central
    • Google Scholar
  38. 38.

    Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12:298–306.

    • CAS
    • PubMed
    • PubMed Central
    • Article
    • Google Scholar
  39. 39.

    Langers I, Renoux V, Reschner A, Touze A, Coursaget P, Boniver J, et al. Natural killer and dendritic cells collaborate in the immune response induced by the vaccine against uterine cervical cancer. Eur J Immunol. 2014;44:3585–95.

    • CAS
    • PubMed
    • Article
    • Google Scholar
  40. 40.

    Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer. 2012;12:265–77.

    • CAS
    • PubMed
    • PubMed Central
    • Article
    • Google Scholar
  41. 41.

    Knutson KL, Disis ML. Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunol Immunother. 2005;54:721–8.

    • CAS
    • PubMed
    • Article
    • PubMed Central
    • Google Scholar
  42. 42.

    Marichal T, Tsai M, Galli SJ. Mast cells: potential positive and negative roles in tumor biology. Cancer Immunol Res. 2013;1:269–79.

    • CAS
    • PubMed
    • Article
    • PubMed Central
    • Google Scholar

Source: https://bmccancer.biomedcentral.com/articles/10.1186/s12885-019-6202-3

healthyincandyland.com