Enhanced nitric oxide production is a universal response to hypoxic stress

Enhanced nitric oxide production is a universal response to hypoxic stress Life at high altitude poses a formidable challenge to human physiology because every breath of thin air inhaled contains less oxygen (O2) per volume than air at sea level, causing the resultant drop in O2 pressure in blood to limit performance and threaten survival. While short-term adjustments to hypoxia (acclimatization) including increased erythropoiesis ensure total O2 content of blood remains unchanged, body functions at high altitude are severely compromised [1]. Adaptation over millennia has enabled humans to cope with these challenges and, by now, >140 million people live permanently at altitudes above 2500 m in South America (Andeans), East Africa (Ethiopians) and Central Asia (Tibetans). Studying human adaptation to the hypobaric hypoxia of high altitude provides a window into ‘natural selection in action’, showing us ‘what worked’. Understanding the mechanisms involved in (acclimatization and) adaptation to this environmental stressor is not only of significance for evolutionary biology and altitude medicine, but may also help mitigate the adverse health effects associated with spaceflight; moreover, findings from this research may suggest novel treatment modalities for patients with chronic respiratory conditions, ischemic heart disease and those admitted to critical care in the hospital [2]. About a decade ago, Erzurum et al. [3] reported that a higher microcirculatory blood flow, accompanied by elevated levels of nitric oxide (NO) products in blood, offsets high-altitude hypoxia among Tibetans. These observations shifted attention from the traditional focus on blood and lung function to vascular factors contributing to adaptation. Indigenous Tibetans, who settled in the Quinhai-Tibetan plateau >10 000 years ago, are a particularly interesting population to study. Genetic studies identified natural selection on EPAS1 (encoding HIF-2α) and EGLN1 (encoding PDH2), both associated with low hemoglobin concentrations, to have provided Tibetans with a particular resilience against the development of chronic mountain sickness via a blunted erythropoietic response [4,5]. Other large-scale genome-wide studies have provided further insights into hypoxia adaptation in this population [6]. He et al. [7] followed this lead and extended our knowledge further by offering an evolutionary genetic analysis of the potential drivers underpinning those adaptive changes, including other players such as GCH1 (encoding GTP-cyclohydrolase 1, an enzyme important for the production of tetrahydrobiopterin used by nitric oxide synthase and other enzymes involved in melatonin and neurotransmitter/hormone production) [8] and others that appear to have undergone both positive and negative selection. Comparing Tibetan highlanders with (acclimatized) Han-Chinese at three different altitudes, this study [7] is impressive by its sheer magnitude and the overall number of blood samples analysed. While the genetic analyses are robust and informative, some of the conclusions drawn from the measurement of NO products in the serum samples collected deserve further comment. He et al. [7] found that circulating levels of the oxidative NO metabolite nitrate (NO3−) are robustly elevated in high-altitude dwellers at all elevations (in biology, NOx typically denotes the sum of nitrite (NO2−) and nitrate, but the authors seem to mean ‘any NO metabolite’; in any case, nitrate accounts for >95% of the NOx signal). This is consistent with earlier observations demonstrating increased NO metabolites in blood of Tibetan highlanders compared to an American sea-level cohort [3] and Caucasian lowlanders sojourning to high altitude [9,10]. Contrary to hemoglobin, He et al. [7] also observed that NOx concentrations did not progressively rise with increasing altitude, but peaked at an intermediate elevation of 3660 m. This is consistent with findings in Caucasian lowlanders trekking to Everest Base Camp [9], whose plasma concentrations of nitrite, nitrate and cGMP all peaked at 3500 m. More recent studies demonstrated additional metabolic adaptations in O2 and fatty acid utilization by skeletal muscle mitochondria, with unique differences between Caucasian lowlanders and Sherpas using an identical ascent profile [11]. Notably, in this study, the Sherpas—a population of Tibetan descent with superior performance in elite climbing at extreme altitudes—did not reveal those marked elevations in NO metabolites observed in other Tibetan highlanders [3] before. He et al.’s conclusion, based on a comparison of steady-state concentrations of NOx in serum of Han-Chinese and Tibetans residing at altitudes between 1900 and 3660 m, that Tibetans have a ‘blunted NO regulation’ (compared to Han-Chinese) [7] is unfortunate and not supported by their own data. Likewise, the speculation that the slightly higher NOx levels in Han-Chinese residing at 3660 m may contribute to toxicity is inconsistent with a large body of more recent evidence to the contrary [12,13]. Of note, there was no difference in serum NOx levels in residents of either ancestry at 2118 m and the reverse order to that apparent at 3660 m was found at a more moderate altitude (1990 m). Circulating eNOS protein levels closely matched NOx concentrations up to 3700 m, but diverged at higher elevations (with eNOS further rising and NOx levels gradually decreasing). Instead of a ‘blunted NO response’, this suggests that Tibetans may have evolved ways to enhance renal excretion of NOx (a large part of which is reabsorbed in the kidneys). Alternatively, Tibetans may benefit from increased NOx utilization in hypoxia. To this end, nitrite and nitrate may provide additional NO equivalents following sequential reduction in blood and tissue [12–14]—a process inhibited by oxygen [15] and therefore favoured in hypoxia. Comparative studies testing this paradigm in cultured human umbilical vein endothelial cells of Han-Chinese and Tibetan origin might provide a fruitful avenue for future endeavour. In any case, it is not difficult to understand why Han-Chinese are more stressed by life in chronic hypoxia: they have had far less time to adapt to the high-altitude environment compared to Tibetans. We should, of course, be mindful of the fact that NO is not the only stress response at play here. Along with other reactive nitrogen species (such as .NO2, ONOO− and NO2−), NO production is part of an intricate network also comprising reactive oxygen species (e.g. O2.−, H2O2) and reactive sulfur species (e.g. HSS/HS−, Sx2−, RS.). These and probably other small molecules conspire by interacting chemically and functionally at multiple levels to enable efficient sensing and adaptive regulation in response to changes in environmental conditions [16]. Thus, NO is just one element of this universal ‘reactive species interactome’, which plays an essential role in stress signalling in microbes, plants and mammals. Large-scale genetic analyses, such as those used in the present study, are powerful tools suited to identify/confirm the involvement of specific proteins and pathways in human adaptation to environmental stressors. However, a full appreciation of the significance of individual regulatory elements/pathways will require additional information from other analyses (e.g. metabolomics), complemented by further physiological and pharmacological studies. Since proteins tentatively identified to change under Darwinian selection pressure often fulfil multiple functions, it is challenging to predict the outcome of these interactions in vivo. I am sure Hans Selye, the pioneer of the stress concept in biology, would have loved joining us to witness big questions such as ‘human stress signalling’ being tackled using an integrated ‘omics/functional approach—we are indeed living in most exciting times. References 1. Grocott MP , Martin DS , Levett DZ et al. N Engl J Med 2009 ; 360 : 140 – 9 . CrossRef Search ADS PubMed 2. Grocott M , Montgomery H , Vercueil A. Crit Care 2007 ; 11 : 203 . CrossRef Search ADS PubMed 3. Erzurum SC , Ghosh S , Janocha AJ et al. Proc Natl Acad Sci USA 2007 ; 104 : 17593 – 8 . CrossRef Search ADS PubMed 4. Beall CM , Cavalleri GL , Deng L et al. Proc Natl Acad Sci USA 2010 ; 107 : 11459 – 64 . CrossRef Search ADS PubMed 5. Lorenzo FR , Huff C , Myllymäki M et al. Nat Genet 2014 ; 46 : 951 – 6 . CrossRef Search ADS PubMed 6. Yang J , Jin ZB , Chen J et al. Proc Natl Acad Sci USA 2017 ; 114 : 4189 – 94 . CrossRef Search ADS PubMed 7. He YX , Qi XB , Ouzhuluobu et al. Natl Sci Rev 2018 ; 5 : 516 – 29 . CrossRef Search ADS 8. Guo YB , He YX , Cui CY et al. Zool Res 2017 ; 38 : 155 – 62 . CrossRef Search ADS PubMed 9. Levett DZ , Fernandez BO , Riley HL et al. Sci Rep 2011 ; 1 : 109 . CrossRef Search ADS PubMed 10. Janocha AJ , Koch CD , Tiso M et al. N Engl J Med 2011 ; 365 : 1942 – 4 . CrossRef Search ADS PubMed 11. Horscroft JA , Kotwica AO , Laner V et al. Proc Natl Acad Sci USA 2017 ; 114 : 6382 – 7 CrossRef Search ADS PubMed 12. Butler AR , Feelisch M . Circulation 2008 ; 117 : 2151 – 9 . CrossRef Search ADS PubMed 13. Weitzberg E , Lundberg JO . Annu Rev Nutr 2013 ; 33 : 129 – 59 . CrossRef Search ADS PubMed 14. Lundberg JO , Weitzberg E , Gladwin MT . Nat Rev Drug Discov 2008 ; 7 : 156 – 67 . CrossRef Search ADS PubMed 15. Feelisch M , Fernandez BO , Bryan NS et al. J Biol Chem 2008 ; 283 : 33927 – 34 . CrossRef Search ADS PubMed 16. Cortese-Krott MM , Koning A , Kuhnle GGC et al. Antioxid Redox Signal 2017 ; 27 : 684 – 712 . CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png National Science Review Oxford University Press

Enhanced nitric oxide production is a universal response to hypoxic stress

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Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd.
ISSN
2095-5138
eISSN
2053-714X
D.O.I.
10.1093/nsr/nwy041
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Abstract

Life at high altitude poses a formidable challenge to human physiology because every breath of thin air inhaled contains less oxygen (O2) per volume than air at sea level, causing the resultant drop in O2 pressure in blood to limit performance and threaten survival. While short-term adjustments to hypoxia (acclimatization) including increased erythropoiesis ensure total O2 content of blood remains unchanged, body functions at high altitude are severely compromised [1]. Adaptation over millennia has enabled humans to cope with these challenges and, by now, >140 million people live permanently at altitudes above 2500 m in South America (Andeans), East Africa (Ethiopians) and Central Asia (Tibetans). Studying human adaptation to the hypobaric hypoxia of high altitude provides a window into ‘natural selection in action’, showing us ‘what worked’. Understanding the mechanisms involved in (acclimatization and) adaptation to this environmental stressor is not only of significance for evolutionary biology and altitude medicine, but may also help mitigate the adverse health effects associated with spaceflight; moreover, findings from this research may suggest novel treatment modalities for patients with chronic respiratory conditions, ischemic heart disease and those admitted to critical care in the hospital [2]. About a decade ago, Erzurum et al. [3] reported that a higher microcirculatory blood flow, accompanied by elevated levels of nitric oxide (NO) products in blood, offsets high-altitude hypoxia among Tibetans. These observations shifted attention from the traditional focus on blood and lung function to vascular factors contributing to adaptation. Indigenous Tibetans, who settled in the Quinhai-Tibetan plateau >10 000 years ago, are a particularly interesting population to study. Genetic studies identified natural selection on EPAS1 (encoding HIF-2α) and EGLN1 (encoding PDH2), both associated with low hemoglobin concentrations, to have provided Tibetans with a particular resilience against the development of chronic mountain sickness via a blunted erythropoietic response [4,5]. Other large-scale genome-wide studies have provided further insights into hypoxia adaptation in this population [6]. He et al. [7] followed this lead and extended our knowledge further by offering an evolutionary genetic analysis of the potential drivers underpinning those adaptive changes, including other players such as GCH1 (encoding GTP-cyclohydrolase 1, an enzyme important for the production of tetrahydrobiopterin used by nitric oxide synthase and other enzymes involved in melatonin and neurotransmitter/hormone production) [8] and others that appear to have undergone both positive and negative selection. Comparing Tibetan highlanders with (acclimatized) Han-Chinese at three different altitudes, this study [7] is impressive by its sheer magnitude and the overall number of blood samples analysed. While the genetic analyses are robust and informative, some of the conclusions drawn from the measurement of NO products in the serum samples collected deserve further comment. He et al. [7] found that circulating levels of the oxidative NO metabolite nitrate (NO3−) are robustly elevated in high-altitude dwellers at all elevations (in biology, NOx typically denotes the sum of nitrite (NO2−) and nitrate, but the authors seem to mean ‘any NO metabolite’; in any case, nitrate accounts for >95% of the NOx signal). This is consistent with earlier observations demonstrating increased NO metabolites in blood of Tibetan highlanders compared to an American sea-level cohort [3] and Caucasian lowlanders sojourning to high altitude [9,10]. Contrary to hemoglobin, He et al. [7] also observed that NOx concentrations did not progressively rise with increasing altitude, but peaked at an intermediate elevation of 3660 m. This is consistent with findings in Caucasian lowlanders trekking to Everest Base Camp [9], whose plasma concentrations of nitrite, nitrate and cGMP all peaked at 3500 m. More recent studies demonstrated additional metabolic adaptations in O2 and fatty acid utilization by skeletal muscle mitochondria, with unique differences between Caucasian lowlanders and Sherpas using an identical ascent profile [11]. Notably, in this study, the Sherpas—a population of Tibetan descent with superior performance in elite climbing at extreme altitudes—did not reveal those marked elevations in NO metabolites observed in other Tibetan highlanders [3] before. He et al.’s conclusion, based on a comparison of steady-state concentrations of NOx in serum of Han-Chinese and Tibetans residing at altitudes between 1900 and 3660 m, that Tibetans have a ‘blunted NO regulation’ (compared to Han-Chinese) [7] is unfortunate and not supported by their own data. Likewise, the speculation that the slightly higher NOx levels in Han-Chinese residing at 3660 m may contribute to toxicity is inconsistent with a large body of more recent evidence to the contrary [12,13]. Of note, there was no difference in serum NOx levels in residents of either ancestry at 2118 m and the reverse order to that apparent at 3660 m was found at a more moderate altitude (1990 m). Circulating eNOS protein levels closely matched NOx concentrations up to 3700 m, but diverged at higher elevations (with eNOS further rising and NOx levels gradually decreasing). Instead of a ‘blunted NO response’, this suggests that Tibetans may have evolved ways to enhance renal excretion of NOx (a large part of which is reabsorbed in the kidneys). Alternatively, Tibetans may benefit from increased NOx utilization in hypoxia. To this end, nitrite and nitrate may provide additional NO equivalents following sequential reduction in blood and tissue [12–14]—a process inhibited by oxygen [15] and therefore favoured in hypoxia. Comparative studies testing this paradigm in cultured human umbilical vein endothelial cells of Han-Chinese and Tibetan origin might provide a fruitful avenue for future endeavour. In any case, it is not difficult to understand why Han-Chinese are more stressed by life in chronic hypoxia: they have had far less time to adapt to the high-altitude environment compared to Tibetans. We should, of course, be mindful of the fact that NO is not the only stress response at play here. Along with other reactive nitrogen species (such as .NO2, ONOO− and NO2−), NO production is part of an intricate network also comprising reactive oxygen species (e.g. O2.−, H2O2) and reactive sulfur species (e.g. HSS/HS−, Sx2−, RS.). These and probably other small molecules conspire by interacting chemically and functionally at multiple levels to enable efficient sensing and adaptive regulation in response to changes in environmental conditions [16]. Thus, NO is just one element of this universal ‘reactive species interactome’, which plays an essential role in stress signalling in microbes, plants and mammals. Large-scale genetic analyses, such as those used in the present study, are powerful tools suited to identify/confirm the involvement of specific proteins and pathways in human adaptation to environmental stressors. However, a full appreciation of the significance of individual regulatory elements/pathways will require additional information from other analyses (e.g. metabolomics), complemented by further physiological and pharmacological studies. Since proteins tentatively identified to change under Darwinian selection pressure often fulfil multiple functions, it is challenging to predict the outcome of these interactions in vivo. I am sure Hans Selye, the pioneer of the stress concept in biology, would have loved joining us to witness big questions such as ‘human stress signalling’ being tackled using an integrated ‘omics/functional approach—we are indeed living in most exciting times. References 1. Grocott MP , Martin DS , Levett DZ et al. N Engl J Med 2009 ; 360 : 140 – 9 . CrossRef Search ADS PubMed 2. Grocott M , Montgomery H , Vercueil A. Crit Care 2007 ; 11 : 203 . CrossRef Search ADS PubMed 3. Erzurum SC , Ghosh S , Janocha AJ et al. Proc Natl Acad Sci USA 2007 ; 104 : 17593 – 8 . CrossRef Search ADS PubMed 4. Beall CM , Cavalleri GL , Deng L et al. Proc Natl Acad Sci USA 2010 ; 107 : 11459 – 64 . CrossRef Search ADS PubMed 5. Lorenzo FR , Huff C , Myllymäki M et al. Nat Genet 2014 ; 46 : 951 – 6 . CrossRef Search ADS PubMed 6. Yang J , Jin ZB , Chen J et al. Proc Natl Acad Sci USA 2017 ; 114 : 4189 – 94 . CrossRef Search ADS PubMed 7. He YX , Qi XB , Ouzhuluobu et al. Natl Sci Rev 2018 ; 5 : 516 – 29 . CrossRef Search ADS 8. Guo YB , He YX , Cui CY et al. Zool Res 2017 ; 38 : 155 – 62 . CrossRef Search ADS PubMed 9. Levett DZ , Fernandez BO , Riley HL et al. Sci Rep 2011 ; 1 : 109 . CrossRef Search ADS PubMed 10. Janocha AJ , Koch CD , Tiso M et al. N Engl J Med 2011 ; 365 : 1942 – 4 . CrossRef Search ADS PubMed 11. Horscroft JA , Kotwica AO , Laner V et al. Proc Natl Acad Sci USA 2017 ; 114 : 6382 – 7 CrossRef Search ADS PubMed 12. Butler AR , Feelisch M . Circulation 2008 ; 117 : 2151 – 9 . CrossRef Search ADS PubMed 13. Weitzberg E , Lundberg JO . Annu Rev Nutr 2013 ; 33 : 129 – 59 . CrossRef Search ADS PubMed 14. Lundberg JO , Weitzberg E , Gladwin MT . Nat Rev Drug Discov 2008 ; 7 : 156 – 67 . CrossRef Search ADS PubMed 15. Feelisch M , Fernandez BO , Bryan NS et al. J Biol Chem 2008 ; 283 : 33927 – 34 . CrossRef Search ADS PubMed 16. Cortese-Krott MM , Koning A , Kuhnle GGC et al. Antioxid Redox Signal 2017 ; 27 : 684 – 712 . CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

National Science ReviewOxford University Press

Published: Jul 1, 2018

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