SpringerLink
Log in

High-altitude hypoxia induced reactive oxygen species generation, signaling, and mitigation approaches

  • Review Paper
  • Published:
International Journal of Biometeorology Aims and scope Submit manuscript

Abstract

Homeostasis between pro-oxidants and anti-oxidants is necessary for aerobic life, which if perturbed and shifted towards pro-oxidants results in oxidative stress. It is generally agreed that reactive oxygen species (ROS) production is accelerated with mountainous elevation, which may play a role in spawning serious health crisis. Exposure to increasing terrestrial altitude leads to a reduction in ambient O2 availability in cells producing a series of hypoxic oxidative stress reactions and altering the redox balance in humans. Enormous literature on redox signaling drove research activity towards understanding the role of oxidative stress under normal and challenging conditions like high-altitude hypoxia which grounds for disturbed redox signaling. Excessive ROS production and accumulation of free radicals in cells and tissues can cause various pulmonary, cardiovascular, and metabolic pathophysiological conditions. In order to counteract this oxidative stress and maintain the balance of pro-oxidants and anti-oxidants, an anti-oxidant system exists in the human body, which, however, gets surpassed by elevated ROS levels, but can be strengthened through the use of anti-oxidant supplements. Such cumulative studies of fundamentals on a global concept like oxidative stress and role of anti-oxidants can act as a foundation to further smoothen for researchers to study over health, disease, and other pathophysiological conditions. This review highlights the interconnection between high altitude and oxidative stress and the role of anti-oxidants to protect cells from oxidative damages and to lower the risk of altitude-associated sickness.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Agani FH, Pichiule P, Chavez JC, LaMann JC (2000) The role of mitochondria in the regulation of hypoxia-inducible factor 1 expression during hypoxia. J Biol Chem 275:35863–35867

    CAS  Google Scholar 

  • Ames BN, Shigenaga MK, Hagen TM (1995) Mitochondrial decay in aging. Biochim Biophys Acta 1271:165–170

    Google Scholar 

  • Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL, Pugh CW, Ratcliffe PJ, Gleadle JM (2004) Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia inducible factor. J Biol Chem 279:38458–38465

    CAS  Google Scholar 

  • Araneda OF, García C, Lagos N, Quiroga G, Cajigal J, Salazar MP, Behn C (2005) Lung oxidative stress as related to exercise and altitude. Lipid peroxidation evidence in exhaled breath condensate: a possible predictor of acute mountain sickness. Eur J Appl Physiol 95:383–390

    CAS  Google Scholar 

  • Askew EW (1995) Environmental and physical stress and nutrient requirements. Am J Clin Nutr 61:631S–637S

    CAS  Google Scholar 

  • Askew EW (1997) Nutrition and performance in hot, cold, and high altitude environments. In: Wolinsky I (ed) Nutrition in exercise and sport, 3rd edn. CRC Press, Boca Raton, pp 597–619

    Google Scholar 

  • Bailey DM, Davies B (1997) Physiological implications of altitude training for endurance performance at sea level: a review. Br J Sports Med 31:183–190

    CAS  Google Scholar 

  • Bailey DM, Davies B (2001) Acute mountain sickness; prophylactic benefits of antioxidant vitamin supplementation at high altitude. High Alt Med Biol 2:21–29

    CAS  Google Scholar 

  • Bailey DM, Davies B, Young IS (2000) Evidence for reactive oxidant generation during physical exercise and normobaric hypoxia in man. J Physiol C27:47P

  • Baillie JK, Bates MG, Thompson AA, Waring WS, Partridge RW, Schnopp MF, Simpson A, Gulliver-Sloan F, Maxwell SR, Webb DJ (2007) Endogenous urate production augments plasma antioxidant capacity in healthy lowland subjects exposed to high altitude. Chest 131:1473–1478

    CAS  Google Scholar 

  • Baillie JK, Thompson AA, Irving JB, Bates MG, Sutherland AI, Macnee W, Maxwell SR, Webb DJ (2009) Oral antioxidant supplementation does not prevent acute mountain sickness: double blind randomized placebo-controlled trial. QJM 102:341–348

    CAS  Google Scholar 

  • Barhwal K, Singh SB, Hota SK, Jayalakshmi K, Ilavazhagan G (2007) Acetyl-L-Carnitine ameliorates hypobaric hypoxic impairment and spatial memory deficits in rats. Eur J Pharmacol 570:97–107

    CAS  Google Scholar 

  • Bautista-Ortega J, Ruiz-Feria CA (2010) L-arginine and antioxidant vitamins E and C improve the cardiovascular performance of broiler chickens grown under chronic hypobaric hypoxia. Poult Sci 89:2141–2146

    CAS  Google Scholar 

  • Bell EL, Emerling BM, Ricoult SJ, Guarente L (2011) SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production. Oncogene 30:2986–2996

    CAS  Google Scholar 

  • Bernabucci U, Ronchi B, Lacetera N, Nardone A (2002) Markers of oxidative status in plasma and erythrocytes of transition dairy cows during hot season. J Dairy Sci 85:2173–2179

    CAS  Google Scholar 

  • Berra E, Benizri E, Ginouvès A, Volmat V, Roux D, Pouysségur J (2003) HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1a in normoxia. EMBO J 22:4082–4090

    CAS  Google Scholar 

  • Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O (2012) Oxidative stress and antioxidant defense. World Allergy Organ J 5:9–19

    CAS  Google Scholar 

  • Botao Y, Ma J, **ao W, **ang Q, Fan K, Hou J, Wu J, **g W (2013) Protective effect of ginkgolide B on high altitude cerebral edema of rats. High Alt Med Biol 14:61–64

    Google Scholar 

  • Boveris A, Cadenas E (1982) Production of superoxide radicals and hydrogen peroxide in mitochondria. In: Oberley LW (ed) Superoxide dismutase. CRC Press, Boca Raton, pp 15–30

    Google Scholar 

  • Brooks GA, Fahey TD, White TP, Baldwin K (1999) Exercise, atmospheric pressure, air pollution, and travel. In: Exercise Physiology. Mayfield, Mountain View, CA ; pp 504–536

  • Bunn HF, Poyton RO (1996) Oxygen sensing and molecular adaptation to hypoxia. Physiol Rev 76:839–885

    CAS  Google Scholar 

  • Chandel NS, Budinger GRS, Choe SH, Schumacker PT (1997) Cellular respiration during hypoxia: role of cytochrome oxidase as the oxygen sensor in hepatocytes. J Biol Chem 272:111–112

    Google Scholar 

  • Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT (1998) Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci 95:11715–11720

    CAS  Google Scholar 

  • Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT (2000) Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1a during hypoxia: a mechanism of O2 sensing. J Biol Chem 275:25130–25138

    CAS  Google Scholar 

  • Chang SW, Stelzner TJ, Weil JV, Voelkel NF (1989) Hypoxia increases plasma glutathione disulfide in rats. Lung 167:269–276

    CAS  Google Scholar 

  • Chao W, Askew EW, Roberts DE, Wood SM, Perkins JB (1999) Oxidative stress in human during work at moderate altitude. J Nutr 129:2009–2012

    CAS  Google Scholar 

  • Cross CE, Halliwell B, Borish ET, Pryor WA, Ames BN, Saul RL, McCord JM, Harman D (1987) Oxygen radicals and human disease. Ann Int Med 107:526–545

    CAS  Google Scholar 

  • Cymerman A (1996) The physiology of high-altitude exposure. In: Marriott BM, Carlson SJ (eds) Nutritional needs in cold and high-altitude environments. National Academy Press, Washington, DC, pp 295–317

    Google Scholar 

  • Debevec T, Millet GP, Pialoux V (2017) Hypoxia-induced oxidative stress modulation with physical activity. Front Physiol 8:84

    Google Scholar 

  • Dosek A, Ohno H, Acs Z, Taylor AW, Radak Z (2007) High altitude and oxidative stress. Respir Physiol Neurobiol 158:128–131

    CAS  Google Scholar 

  • Finkel T (2011) Signal transduction by reactive oxygen species. J Cell Biol 194:7–15

    CAS  Google Scholar 

  • Friedman JK, Nitta CH, Henderson KM, Codianni SJ, Sanchez L, Ramiro-Diaz JM, Howard TA, Giermakowska W, Kanagy NL, Gonzalez Bosc LV (2014) Intermittent hypoxia-induced increases in reactive oxygen species activate NFATc3 increasing endothelin-1 vasoconstrictor reactivity. Vasc Pharmacol 60(1):17–24

    CAS  Google Scholar 

  • Gangwar A, Paul S, Ahmad Y, Bhargava K (2020) Intermittent hypoxia modulates redox homeostasis, lipid metabolism associated inflammatory processes and redox post-translational modifications: benefits at high altitude. Sci Rep 10:7899

    CAS  Google Scholar 

  • Gertsch JH, Basnyat B, Johnson EW, Onopa J, Holck PS (2004) Randomised, double blind, placebo controlled comparison of Ginkgo Biloba and acetazolamide for prevention of acute mountain sickness among Himalayan trekkers: the prevention of high altitude illness trial (PHAIT). BMJ 328:797

    CAS  Google Scholar 

  • Glasauer A, Chandel NS (2013) ROS. Curr Biol 23:R100–R102

    CAS  Google Scholar 

  • Goldfarb AH, Sen CK (1994) Antioxidant-supplementation and control of oxygen. In: Sen CK, Packer L, Osmo H (eds) Exercise and oxygen toxicity. Elsevier, New York, pp 163–190

    Google Scholar 

  • Güzel NA, Sayan H, Erbas D (2000) Effects of moderate altitude on exhaled nitric oxide, erythrocytes lipid peroxidation and superoxide dismutase levels. Med Sci Sports Exerc Jpn J Physiol 50:187–190

    Google Scholar 

  • Guzy RD, Schumacker PT (2006) Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia. Exp Physiol 91:807–819

    CAS  Google Scholar 

  • Guzy RD, Hoyos B, Robin E, Chen H, Liu L, Mansfield KD, Simon MC, Hammerling U, Schumacker PT (2005) Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab 1:401–408

    CAS  Google Scholar 

  • Hagobian TA, Jacobs KA, Subudhi AW, Fattor JA, Rock PB, Muza SR, Fulco CS, Braun B, Grediagin A, Mazzeo RS, Cymerman A, Friedlander AL (2006) Cytokine responses at high altitude: effects of exercise and antioxidants at 4300 m. Med Sci Sports Exerc 38:276–285

    CAS  Google Scholar 

  • Halliwell B (2011) Free radicals and antioxidants-quo vadis? Trends Pharmacol Sci 32:125–130

    CAS  Google Scholar 

  • Hamanaka RB, Chandel NS (2010) Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes. Trends Biochem Sci 35(9):505–513

    CAS  Google Scholar 

  • Hoppeler H, Vogt M (2001) Muscle tissue adaptations to hypoxia. J Exp Biol 204:3133–3139

    CAS  Google Scholar 

  • Hornbein TF (2001) The high-altitude brain. J Exp Biol 204:3129–3132

    CAS  Google Scholar 

  • Huang HC, Nguyen T, Pickett CB (2002) Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription. J Biol Chem 277:42769–42774

    CAS  Google Scholar 

  • Huey RB, Eguskitza X (2001) Limits to human performance: elevated risks on high mountains. J Exp Biol 204:3115–3119

    CAS  Google Scholar 

  • Hultgren H (1997) High altitude medicine. Hultgren Publications, Stanford

    Google Scholar 

  • Innamorato NG, Rojo AI, Garcıa-Yague AJ, Yamamoto M, De Ceballos ML, Cuadrado A (2008) The transcription factor Nrf2 is a therapeutic target against brain inflammation. J Immunol 181:680–689

    CAS  Google Scholar 

  • Irarrázaval S, Allard C, Campodónico J, Pérez D, Strobel P, Vásquez L, Urquiaga I, Echeverría G, Leighton F (2017) Oxidative stress in acute hypobaric hypoxia. High Alt Med Biol 18(2):128-134  

  • Janocha AJ, Comhair SAA, Basnyat B, Neupane M, Gebremedhin A, Khan A, Ricci KS, Zhang R, Erzurum SC, Beall CM (2017) Antioxidant defense and oxidative damage vary widely among high- altitude residents. Am J Hum Biol 29(6):1–10

    Google Scholar 

  • Jefferson JA, Simoni J, Escudero E, Hurtado ME, Swenson ER, Wesson DE, Schreiner GF, Schoene RB, Johnson RJ, Hurtado A (2004) Increased oxidative stress following acute and chronic high altitude exposure. High Alt Med Biol 5:61–69

    CAS  Google Scholar 

  • Jiang C, Cui J, Liu F, Gao L, Luo Y, Li P, Guan L, Gao Y (2014) Mitochondrial DNA 10609t promotes hypoxia-induced increase of intracellular ROS and is a risk factor of high altitude polycythemia. PLoS One 9:e87775

    Google Scholar 

  • Joanny P, Steinberg J, Robach P, Richalet JP, Gortan C, Gradette B, Jammes Y (2001) Operation Everest III (Comex’97): the effect of simulated severe hypobaric hypoxia on blood lipid peroxidation and antioxidant defence systems in human blood at rest and after maximal exercise. Resuscitation 49:307–314

    CAS  Google Scholar 

  • Kappus H (1985) Lipid peroxidation mechanism, analysis, enzymology and biological relevance. In: Sies H (ed) Oxidative stress. Academic Press, London, pp 273–310

    Google Scholar 

  • Kensler TW, Wakabayashi N, Biswal S (2007) Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 47:89–116

    CAS  Google Scholar 

  • Kietzmann T, Görlach A (2005) Reactive oxygen species in the control of hypoxia inducible factor-mediated gene expression. Semin Cell Dev Biol 16:474–486

    CAS  Google Scholar 

  • Koivisto AE, Olsen T, Paur I, Paulsen G, Bastani NE, Garthe I, Raastad T, Matthews J, Blomhoff R, Bøhn SK (2019) Effects of antioxidant-rich foods on altitude-induced oxidative stress and inflammation in elite endurance athletes: a randomized controlled trial. PLoS One 14(6):e0217895. https://doi.org/10.1371/journal.pone.0217895

    Article  CAS  Google Scholar 

  • Kovac S, Angelova PR, Holmstrom KM, Zhang Y, Dinkova-Kostova AT, Abramov AY (2015) Nrf2 regulates ROS production by mitochondria and NADPH oxidase. Biochim Biophys Acta 1850:794–801

    CAS  Google Scholar 

  • Kumar J, Khan S, Mandotra SK, Dhar P, Tayade AB, Verma S et al (2019) Nutraceutical profile and evidence of alleviation of oxidative stress by Spirogyra porticalis (Muell.) Cleve inhabiting the high altitude Trans-Himalayan Region. Sci Rep 9:4091. https://doi.org/10.1038/s41598-018-35595-x

    Article  CAS  Google Scholar 

  • Kunwar A, Priyadarsini KI (2011) Free radicals, oxidative stress and importance of antioxidants in human health. J Med Allied Sci 1:53–60

    Google Scholar 

  • Lance S, Piermattei TD, Shibao GN, McManaman JL, Wright RM (1997) Hypoxia regulates xanthine dehydrogenase activity at pre- and posttranslational levels. Arch Biochem Biophy 348:163–168

    Google Scholar 

  • Lanzillo JJ, Yu FS, Stevens J, Hassoun PM (1996) Determination of xanthine dehydrogenase mRNA by a reverse transcription-coupled competitive quantitative polymerase chain reaction assay: regulation in rat endothelial cells by hypoxia and hyperoxia. Arch Biochem Biophy 335:377–380

    CAS  Google Scholar 

  • Lee JM, Shih AY, Murphy TH, Johnson JA (2003) NF-E2-related factor-2 mediates neuroprotection against mitochondrial complex I inhibitors and increased concentrations of intracellular calcium in primary cortical neurons. J Biol Chem 278:37948–37956

    CAS  Google Scholar 

  • Lemoine AJ, Revollo S, Villalpando G, Valverde I, Gonzales M, Laouafa S, Soliz J, Joseph V (2018) Divergent mitochondrial antioxidant activities and lung alveolar architecture in the lungs of rats and mice at high altitude. Front Physiol 9:311

    Google Scholar 

  • Lewis DFV (2002) Oxidative stress: the role of cytochromes P450 in oxygen activation. J Chem Technol Biotechnol 77:1095–1100

    CAS  Google Scholar 

  • Lin SJ, Guarente L (2003) Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease. Curr Opin Cell Biol 15:241–246

    CAS  Google Scholar 

  • Liu JQ, Zelko IN, Erbynn EM, Sham JSK, Folz RJ (2006) Hypoxic pulmonary hypertension: role of superoxide and NADPH oxidase (gp91phox). Am J Phys 290:L2–L10

    CAS  Google Scholar 

  • Lochhead JJ, Ronaldson PT, Davis TP (2017) Hypoxic stress and inflammatory pain disrupt blood-brain barrier tight junctions: implications for drug delivery to the central nervous system. AAPS J 19(4):910–920

    CAS  Google Scholar 

  • Magalhaes J, Ascensao A, Viscor G, Soares J, Oliveira J, Marques F, Duarte J (2004) Oxidative stress in humans during and after 4 hours of hypoxia at a simulated altitude of 5500 m. Aviat Space Environ Med 75:16–22

    CAS  Google Scholar 

  • Magalhães J, Ascensão A, Marques F, Soares JM, Ferreira R, Neuparth MJ, Duarte JA (2005) Effect of a high-altitude expedition to a Himalayan peak (Pumori, 7,161 m) on plasma and erythrocyte antioxidant profile. Eur J Appl Physiol 93:726–732

    Google Scholar 

  • Malec V, Gottschald OR, Li S, Rose F, Seeger W, Hänze J (2010) HIF1 alpha signaling is augmented during intermittent hypoxia by induction of the Nrf2 pathway in NOX1-expressing adenocarcinoma A549 cells. Free Radic Biol Med 48:1626–1635

    CAS  Google Scholar 

  • Martindale JL, Holbrook NJ (2002) Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol 192:1–15

    CAS  Google Scholar 

  • Masella R, Di Benedetto R, Vari R, Filesi C, Giovannini C (2005) Novel mechanisms of natural antioxidant compounds in biological systems: involvement of glutathione and glutathione-related enzymes. J Nutr Biochem 16:577–586

    CAS  Google Scholar 

  • Mohanraj P, Merola AJ, Wright VP, Clanton TL (1998) Antioxidants protect rat diaphragmatic muscle function under hypoxic conditions. J Appl Physiol 84:1960–1966

    CAS  Google Scholar 

  • Moller P, Loft S, Lundby C, Olsen NV (2001) Acute hypoxia and hypoxic exercise induce DNA strand breaks and oxidative DNA damage in humans. FASEB J 15:1181–1186

    CAS  Google Scholar 

  • Muller FL, Liu Y, VanRemmen H (2004) Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem 279:49064–49073

    CAS  Google Scholar 

  • Murray AJ (2009) Metabolic adaptation of skeletal muscle to high altitude hypoxia: how new technologies could resolve the controversies. Genome Med 1:117

    Google Scholar 

  • Neubauer J (2001) Invited review: physiological and pathological responses to intermittent hypoxia. Am J Phys 90:1593–1599

    CAS  Google Scholar 

  • Oh YS, Jun HS (2017) Effects of glucagon-like peptide-1 on oxidative stress and Nrf2 signaling. Int J Mol Sci 19:E26

    Google Scholar 

  • OHagan KA, Cocchiglia S, Zhdanov AV, Tambuwala MM, Cummins EP, Monfared M, Agbor TA, Garvey JF, Papkovsky DB, Taylor CT, Allan BB (2009) PGC-1alpha is coupled to HIF-1alpha-dependent gene expression by increasing mitochondrial oxygen consumption in skeletal muscle cells. Proc Natl Acad Sci 106:2188–2193

    CAS  Google Scholar 

  • Paddenberg R, Ishaq B, Goldenberg A, Faulhammer P, Rose F, Weissmann N, Braun-Dullaeus RC, Kummer W (2003) Essential role of complex II of the respiratory chain in hypoxia-induced ROS generation in the pulmonary vasculature. Am J Physiol Lung Cell Mol Physiol 284:L710–L719

    CAS  Google Scholar 

  • Parraguez VH, Atlagich M, Araneda O, García C, Muñoz A, De Los Reyes M, Urquieta B (2011) Effects of antioxidant vitamins on newborn and placental traits in gestations at high altitude: comparative study in high and low altitude native sheep. Reprod Fertil Dev 23:285–296

    CAS  Google Scholar 

  • Patir H, Sarada SKS, Singh S, Mathew T, Singh B, Bansal A (2012) Quercetin as a prophylactic measure against high altitude cerebral edema. Free Radic Biol Med 53:659–668

    CAS  Google Scholar 

  • Patterson C, Nageswara NR, Runge MS (2000) The oxidative paradox: another piece in the puzzle. Circ Res 87:1074–1076

    CAS  Google Scholar 

  • Pfeiffer JM, Askew EW, Roberts DE, Wood SM, Benson JE, Johnson SC, Freedman MS (1999) Effect of antioxidant supplementation on urine and blood markers of oxidative stress during extended moderate-altitude training. Wilderness Environ Med 10:66–74

    CAS  Google Scholar 

  • Pialoux V, Mounier R, Brown AD, Steinback CD, Rawling JM, Poulin MJ (2009) Relationship between oxidative stress and HIF-1 alpha mRNA during sustained hypoxia in humans. Free Radic Biol Med 46:321–326

    CAS  Google Scholar 

  • Piantadosi CA, Carraway MS, Babiker A, Suliman HB (2008) Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ Res 103:1232–1240

    CAS  Google Scholar 

  • Poljsak B, Suput D, Milisav I (2013) Achieving the balance between ROS and antioxidants: when to use the synthetic antioxidants. Oxidative Med Cell Longev 2013:1–11. https://doi.org/10.1155/2013/956792

    Article  CAS  Google Scholar 

  • Poss WB, Huecksteadt TP, Panus PC, Freeman BA, Hoidal JR (1996) Regulation of xanthine dehydrogenase and xanthine oxidase activity by hypoxia. Am J Phys 270:L941–L946

    CAS  Google Scholar 

  • Poyton RO, Ball KA, Castello PR (2009) Mitochondrial generation of free radicals and hypoxic signalling. Trends Endocrinol Metabol 20:332–340

    CAS  Google Scholar 

  • Radak Z, Zhao Z, Koltai E, Ohno H, Atalay M (2013) Oxygen consumption and usage during physical exercise: the balance between oxidative stress and ROS-dependent adaptive signaling. Antioxid Redox Signal 18:1208–1246

    CAS  Google Scholar 

  • Ramazan MS, Ekeroglu SH, Dulger H, Algun E (2000) The effect of dietary treatment on erythrocyte lipid peroxidation, superoxide dismutase, glutathione peroxidase, and serum lipid peroxidation in patients with type 2 diabetes mellitus. Clin Biochem 33:669–674

    Google Scholar 

  • Richter C, Park JW, Ames BN (1988) Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci 85:6465–6467

    CAS  Google Scholar 

  • Richter C, Gogvadze V, Laffranchi R, Schlapbach R, Schweizer M, Suter M, Walter P, Yaffee M (1995) Oxidants in mitochondria: from physiology to diseases. Biochim Biophys Acta 1271:67–74

    Google Scholar 

  • Roach RC, Hackett PH (2001) Frontiers of hypoxia research: acute mountain sickness. J Exp Biol 204:3161–3170

    CAS  Google Scholar 

  • Roach RC, Maes D, Sandoval D, Robergs RA, Icenogle M, Hinghofer-Szalky HH, Lium D, Loeppky JA (2000) Exercise exacerbates acute mountain sickness at simulated high altitude. J Appl Physiol 88:581–585

    CAS  Google Scholar 

  • Rosen H, Klebanoff SJ, Wang Y, Brot N, Heinecke JW, Fu X (2009) Methionine oxidation contributes to bacterial killing by the myeloperoxidase system of neutrophils. Proc Natl Acad Sci 106:18686–18691

    CAS  Google Scholar 

  • Rushmore TH, Morton MR, Pickett CB (1991) The antioxidant responsive element: activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem 266:11632–11639

    CAS  Google Scholar 

  • Sarada SKS, Dipti P, Anju B, Pauline T, Kain AK, Sairam M, Sharma SK, Ilavazhagan G, Kumar D, Selvamurthy W (2002) Antioxidant effect of beta-carotene on hypoxia induced oxidative stress in male albino rats. J Ethnopharmacol 79:149–153

    CAS  Google Scholar 

  • Satoh T, Okamoto SI, Cui J, Watanabe Y, Furuta K, Suzuki M, Tohyama K, Lipton SA (2006) Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophilic phase II inducers. Proc Natl Acad Sci 103:768–773

    CAS  Google Scholar 

  • Schieber M, Chandel NS (2014) ROS function in redox signalling and review oxidative stress. Curr Biol 24:R453–R462

    CAS  Google Scholar 

  • Schmidt MC, Askew EW, Roberts DE, Prior RL, Ensign WY Jr, Hesslink RE (2002) Oxidative stress in humans training in a cold, moderate altitude environment and their response to a phytochemical antioxidant supplement. Wilderness Environ Med 13:94–105

    Google Scholar 

  • Schoene RB (2001) Limits of human lung function at high altitude. J Exp Biol 204:3121–3127

    CAS  Google Scholar 

  • Schofield CJ, Ratcliffe PJ (2005) Signalling hypoxia by HIF hydroxylases. Biochem Biophys Res Commun 338:617–626

    CAS  Google Scholar 

  • Sethy NK, Singh M, Kumar R, Ilavazhagan G, Bhargava K (2011) Upregulation of transcription factor NRF2-mediated oxidative stress response pathway in rat brain under short-term chronic hypobaric hypoxia. Funct Integr Genomics 11:119–137

    CAS  Google Scholar 

  • Shinde A, Ganu J, Naik P (2012) Effect of free radicals & antioxidants on oxidative stress: a review. J Dent Allied Sci 1:63–66

    Google Scholar 

  • Shrivastava K, Shukla D, Bansal A, Sairam M, Banerjee PK, Ilavazhagan G (2008) Neuroprotective effect of cobalt chloride on hypobaric hypoxia-induced oxidative stress. Neurochem Int 52:368–375

    CAS  Google Scholar 

  • Sies H (1985) Oxidative stress: introductory remarks. In: Sies H (ed) Oxidative stress. Academic Press, London, pp 1–8

    Google Scholar 

  • Sies H (1986) Biochemistry of oxidative stress. Angew Chem Int Ed Engl 25:1058–1071

    Google Scholar 

  • Sies H (1997) Oxidative stress: oxidants and antioxidants. Exp Physiol 82:291–295

    CAS  Google Scholar 

  • Simon-Schnass I (1994) Risk of oxidative stress during exercise at high altitude. In: Sen CK, Packer L, Hanninen O (eds) Exercise and oxygen toxicity. Elsevier, Amsterdam, pp 191–210

    Google Scholar 

  • Sinha S, Ray US, Tomar OS, Singh SN (2009a) Different adaptation patterns of antioxidant system in natives and sojourners at high altitude. Respir Physiol Neurobiol 167:255–260

    CAS  Google Scholar 

  • Sinha S, Nath S, Singh, Ray US (2009b) Total Antioxidant Status at High Altitude in Lowlanders and Native Highlanders: Role of Uric Acid. High Altitude Medicine & Biology 10 (3):269-274

  • Song TT, Bi YH, Gao YQ, Huang R, Hao K, Xu G, Tang JW, Ma ZQ, Kong FP, Coote JH, Chen XQ, Du JZ (2016) Systemic pro-inflammatory response facilitates the development of cerebral edema during short hypoxia. J Neuroinflammation 13(1):63

    Google Scholar 

  • Stellingwerff T, Peeling P, Garvican-Lewis LA, Hall R, Koivisto AE, Heikura IA, Burke LM (2019) Nutrition and altitude: strategies to enhance adaptation, improve performance and maintain health: a narrative review. Sports Med 49(2):169–184

    Google Scholar 

  • Strapazzon G, Malacrida S, Vezzoli A, Dal Cappello T, Falla M, Lochner P, Moretti S, Procter E, Brugger H, Mrakic-Sposta S (2016) Oxidative stress response to acute hypobaric hypoxia and its association with indirect measurement of increased intracranial pressure: a field study. Sci Rep 6:32426. https://doi.org/10.1038/srep32426

    Article  CAS  Google Scholar 

  • Strom J, Xu B, Tian X, Chen QM, Strom J, Xu B, Tian X, Chen QM (2016) Nrf2 protects mitochondrial decay by oxidative stress. FASEB J 30:66–80

    CAS  Google Scholar 

  • Subudhi AW, Jacobs KA, Hagobian TA, Fattor JA, Muza SR, Fulco CS, Cymerman A, Friedlander AL (2006) Changes in ventilatory threshold at high altitude: effect of antioxidants. Med Sci Sports Exerc 38:1425–1431

    CAS  Google Scholar 

  • Teradat LS, Guidot DM, Leff JA, Willingham IR, Hanley ME, Piermattei D, Repine JE (1992) Hypoxia injures endothelial cells by increasing endogenous xanthine oxidase activity. Proc Natl Acad Sci 89:3362–3366

    Google Scholar 

  • Vani R, Reddy CS, Asha Devi S (2010) Oxidative stress in erythrocytes: a study on the effect of antioxidant mixtures during intermittent exposures to high altitude. Int J Biometeorol 54:553–562

    CAS  Google Scholar 

  • Vats P, Singh VK, Singh SN, Singh SB (2008) Glutathione metabolism under high-altitude stress and effect of antioxidant supplementation. Aviat Space Environ Med 79:1106–1111

    CAS  Google Scholar 

  • Vij AG, Dutta R, Satija NK (2005) Acclimatization to oxidative stress at high altitude. High Alt Med Biol 6:301–310

    CAS  Google Scholar 

  • Wozniak A, Drewa G, Chesy G, Rakowski A, Rozwodowska M, Olszewska D (2001) Effect of altitude training on the peroxidation and antioxidant enzymes in sportsmen. Med Sci Sports Exerc 33:1109–1113

    CAS  Google Scholar 

  • Xu C, Qiao X, Zhao Y, Sun R, Shang X, Niu W (2016) Resveratrol ameliorates chronic high altitude exposure-induced oxidative stress and suppresses lipid metabolism alteration in rats. Eur J Lipid Sci Technol 118:612–621

    CAS  Google Scholar 

  • Yu L, Cao X, Tao W, Li M, Chen L (2020) Antioxidant activity and potential ameliorating effective ingredients for high altitude-induced fatigue from Gansu Maxianhao (Pedicularis Kansuensis Maxim.). J Tradit Chin Med 40(1):83–93

    Google Scholar 

  • Zhang DX, Gutterman DD (2006) Mitochondrial reactive oxygen species-mediated signaling in endothelial cells. Am J Physiol Heart Circ Physiol 292:H2023–H2031

    Google Scholar 

  • Zhang SXL, Wang Y, Gozal D (2012) Pathological consequences of intermittent hypoxia in the central nervous system. Compr Physiol 2:1767–1777

    Google Scholar 

  • Zhong L, D’Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD, Guimaraes A, Marinelli B, Wikstrom JD, Nir T, Clish CB, Vaitheesvaran B, Iliopoulos O, Kurland I, Dor Y, Weissleder R, Shirihai OS, Ellisen LW, Espinosa JM, Mostoslavsky R (2010) The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 140:280–293

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Endocrinology & Metabolism Division, Defence Institute of Physiology and Allied Sciences (DIPAS), DRDO, Lucknow Road, Timarpur, Delhi, 110054,, India

    Priya Gaur, Bhuvnesh Kumar & Praveen Vats

  2. Department of Chemistry, University of Delhi, Delhi, 110007,, India

    Suchita Prasad & Sunil K. Sharma

Authors
  1. Priya Gaur
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Suchita Prasad
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bhuvnesh Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sunil K. Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Praveen Vats
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Sunil K. Sharma or Praveen Vats.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gaur, P., Prasad, S., Kumar, B. et al. High-altitude hypoxia induced reactive oxygen species generation, signaling, and mitigation approaches. Int J Biometeorol 65, 601–615 (2021). https://doi.org/10.1007/s00484-020-02037-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00484-020-02037-1

Keywords

Search

Navigation