Skip to main content

Advertisement

SpringerLink
Log in

Low ambient oxygen prevents atherosclerosis

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

An Erratum to this article was published on 09 March 2016

Abstract

Large population studies have shown that living at higher altitudes, which lowers ambient oxygen exposure, is associated with reduced cardiovascular disease mortality. However, hypoxia has also been reported to promote atherosclerosis by worsening lipid metabolism and inflammation. We sought to address these disparate reports by reducing the ambient oxygen exposure of ApoE−/− mice. We observed that long-term adaptation to 10 % O2 (equivalent to oxygen content at ∼5000 m), compared to 21 % O2 (room air at sea level), resulted in a marked decrease in aortic atherosclerosis in ApoE−/− mice. This effect was associated with increased expression of the anti-inflammatory cytokine interleukin-10 (IL-10), known to be anti-atherogenic and regulated by hypoxia-inducible transcription factor-1α (HIF-1α). Supporting these observations, ApoE−/− mice that were deficient in IL-10 (IL10−/− ApoE−/− double knockout) failed to show reduced atherosclerosis in 10 % oxygen. Our study reveals a specific mechanism that can help explain the decreased prevalence of ischemic heart disease in populations living at high altitudes and identifies ambient oxygen exposure as a potential factor that could be modulated to alter pathogenesis.

Key messages

  • Chronic low ambient oxygen exposure decreases atherosclerosis in mice.

  • Anti-inflammatory cytokine IL-10 levels are increased by low ambient O2.

  • This is consistent with the established role of HIF-1α in IL10 transactivation.

  • Absence of IL-10 results in the loss of the anti-atherosclerosis effect of low O2.

  • This mechanism may contribute to decreased atherosclerosis at high altitudes.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Mortimer EA Jr, Monson RR, MacMahon B (1977) Reduction in mortality from coronary heart disease in men residing at high altitude. N Engl J Med 296:581–585

    Article  PubMed  Google Scholar 

  2. Faeh D, Gutzwiller F, Bopp M (2009) Lower mortality from coronary heart disease and stroke at higher altitudes in Switzerland. Circulation 120:495–501

    Article  PubMed  Google Scholar 

  3. Nakano D, Hayashi T, Tazawa N, Yamashita C, Inamoto S, Okuda N, Mori T, Sohmiya K, Kitaura Y, Okada Y et al (2005) Chronic hypoxia accelerates the progression of atherosclerosis in apolipoprotein E-knockout mice. Hypertens Res 28:837–845

    Article  CAS  PubMed  Google Scholar 

  4. Jun J, Reinke C, Bedja D, Berkowitz D, Bevans-Fonti S, Li J, Barouch LA, Gabrielson K, Polotsky VY (2010) Effect of intermittent hypoxia on atherosclerosis in apolipoprotein E-deficient mice. Atherosclerosis 209:381–386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ross R (1999) Atherosclerosis—an inflammatory disease. N Engl J Med 340:115–126

    Article  CAS  PubMed  Google Scholar 

  6. Palazon A, Goldrath AW, Nizet V, Johnson RS (2014) HIF transcription factors, inflammation, and immunity. Immunity 41:518–528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V et al (2003) HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 112:645–657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Thiel M, Caldwell CC, Kreth S, Kuboki S, Chen P, Smith P, Ohta A, Lentsch AB, Lukashev D, Sitkovsky MV (2007) Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival. PLoS One 2, e853. doi:10.1371/journal.pone.0000853

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kleemann R, Zadelaar S, Kooistra T (2008) Cytokines and atherosclerosis: a comprehensive review of studies in mice. Cardiovasc Res 79:360–376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ben-Shoshan J, Afek A, Maysel-Auslender S, Barzelay A, Rubinstein A, Keren G, George J (2009) HIF-1alpha overexpression and experimental murine atherosclerosis. Arterioscler Thromb Vasc Biol 29:665–670

    Article  CAS  PubMed  Google Scholar 

  11. Sitkovsky M, Lukashev D (2005) Regulation of immune cells by local-tissue oxygen tension: HIF1 alpha and adenosine receptors. Nat Rev Immunol 5:712–721

    Article  CAS  PubMed  Google Scholar 

  12. Wang PY, Ma W, Park JY, Celi FS, Arena R, Choi JW, Ali QA, Tripodi DJ, Zhuang J, Lago CU et al (2013) Increased oxidative metabolism in the Li-Fraumeni syndrome. N Engl J Med 368:1027–1032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kang JG, Amar MJ, Remaley AT, Kwon J, Blackshear PJ, Wang PY, Hwang PM (2011) Zinc finger protein tristetraprolin interacts with CCL3 mRNA and regulates tissue inflammation. J Immunol 187:2696–2701

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W (1993) Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75:263–274

    Article  CAS  PubMed  Google Scholar 

  15. Sung HJ, Ma W, Starost MF, Lago CU, Lim PK, Sack MN, Kang JG, Wang PY, Hwang PM (2011) Ambient oxygen promotes tumorigenesis. PLoS One 6:e19785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Abud EM, Maylor J, Undem C, Punjabi A, Zaiman AL, Myers AC, Sylvester JT, Semenza GL, Shimoda LA (2012) Digoxin inhibits development of hypoxic pulmonary hypertension in mice. Proc Natl Acad Sci U S A 109:1239–1244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Patino WD, Kang JG, Matoba S, Mian OY, Gochuico BR, Hwang PM (2006) Atherosclerotic plaque macrophage transcriptional regulators are expressed in blood and modulated by tristetraprolin. Circ Res 98:1282–1289

    Article  CAS  PubMed  Google Scholar 

  18. Semenza GL, Jiang BH, Leung SW, Passantino R, Concordet JP, Maire P, Giallongo A (1996) Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem 271:32529–32537

    Article  CAS  PubMed  Google Scholar 

  19. Maganto-Garcia E, Tarrio M, Lichtman AH (2012) Mouse models of atherosclerosis. Current protocols in immunology / edited by John E Coligan [et al.] Chapter 15: Unit 15 24 11–23. doi 10.1002/0471142735.im1524s96

  20. West JB (2002) Highest permanent human habitation. High Alt Med Biol 3:401–407

    Article  PubMed  Google Scholar 

  21. Daugherty A (2002) Mouse models of atherosclerosis. Am J Med Sci 323:3–10

    Article  PubMed  Google Scholar 

  22. Caligiuri G, Nicoletti A, Zhou X, Tornberg I, Hansson GK (1999) Effects of sex and age on atherosclerosis and autoimmunity in apoE-deficient mice. Atherosclerosis 145:301–308

    Article  CAS  PubMed  Google Scholar 

  23. Jiang H, Chess L (2006) Regulation of immune responses by T cells. N Engl J Med 354:1166–1176

    Article  CAS  PubMed  Google Scholar 

  24. Cai Z, Luo W, Zhan H, Semenza GL (2013) Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart. Proc Natl Acad Sci U S A 110:17462–17467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Han X, Boisvert WA (2015) Interleukin-10 protects against atherosclerosis by modulating multiple atherogenic macrophage function. Thromb Haemost 113:505–512

    Article  PubMed  Google Scholar 

  26. McAleer JP, Vella AT (2008) Understanding how lipopolysaccharide impacts CD4 T-cell immunity. Crit Rev Immunol 28:281–299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Atkuri KR, Herzenberg LA, Niemi AK, Cowan T (2007) Importance of culturing primary lymphocytes at physiological oxygen levels. Proc Natl Acad Sci U S A 104:4547–4552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ali K, Middleton M, Pure E, Rader DJ (2005) Apolipoprotein E suppresses the type I inflammatory response in vivo. Circ Res 97:922–927

    Article  CAS  PubMed  Google Scholar 

  29. Saraiva M, O’Garra A (2010) The regulation of IL-10 production by immune cells. Nat Rev Immunol 10:170–181

    Article  CAS  PubMed  Google Scholar 

  30. Caligiuri G, Rudling M, Ollivier V, Jacob MP, Michel JB, Hansson GK, Nicoletti A (2003) Interleukin-10 deficiency increases atherosclerosis, thrombosis, and low-density lipoproteins in apolipoprotein E knockout mice. Mol Med 9:10–17

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Mallat Z, Besnard S, Duriez M, Deleuze V, Emmanuel F, Bureau MF, Soubrier F, Esposito B, Duez H, Fievet C et al (1999) Protective role of interleukin-10 in atherosclerosis. Circ Res 85:e17–e24

    Article  CAS  PubMed  Google Scholar 

  32. Eltzschig HK, Carmeliet P (2011) Hypoxia and inflammation. N Engl J Med 364:656–665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Marsch E, Theelen TL, Demandt JA, Jeurissen M, van Gink M, Verjans R, Janssen A, Cleutjens JP, Meex SJ, Donners MM et al (2014) Reversal of hypoxia in murine atherosclerosis prevents necrotic core expansion by enhancing efferocytosis. Arterioscler Thromb Vasc Biol 34:2545–2553

    Article  CAS  PubMed  Google Scholar 

  34. Getz GS, Reardon CA (2015) Use of mouse models in atherosclerosis research. Methods Mol Biol 1339:1–16

    Article  PubMed  Google Scholar 

  35. Meehan RT (1987) Immune suppression at high altitude. Ann Emerg Med 16:974–979

    Article  CAS  PubMed  Google Scholar 

  36. Sitkovsky MV (2009) T regulatory cells: hypoxia-adenosinergic suppression and re-direction of the immune response. Trends Immunol 30:102–108

    Article  CAS  PubMed  Google Scholar 

  37. Lu KY, Ching LC, Su KH, Yu YB, Kou YR, Hsiao SH, Huang YC, Chen CY, Cheng LC, Pan CC et al (2010) Erythropoietin suppresses the formation of macrophage foam cells: role of liver X receptor alpha. Circulation 121:1828–1837

    Article  CAS  PubMed  Google Scholar 

  38. Karagiannidis C, Hense G, Rueckert B, Mantel PY, Ichters B, Blaser K, Menz G, Schmidt-Weber CB (2006) High-altitude climate therapy reduces local airway inflammation and modulates lymphocyte activation. Scand J Immunol 63:304–310

    Article  CAS  PubMed  Google Scholar 

  39. Saeed O, Bhatia V, Formica P, Browne A, Aldrich TK, Shin JJ, Maybaum S (2012) Improved exercise performance and skeletal muscle strength after simulated altitude exposure: a novel approach for patients with chronic heart failure. J Card Fail 18:387–391

    Article  PubMed  Google Scholar 

  40. Stub D, Smith K, Bernard S, Nehme Z, Stephenson M, Bray JE, Cameron P, Barger B, Ellims AH, Taylor AJ et al (2015) Air versus oxygen in ST-segment elevation myocardial infarction. Circulation. doi:10.1161/CIRCULATIONAHA.114.014494

    Google Scholar 

  41. Shehade H, Acolty V, Moser M, Oldenhove G (2015) Cutting edge: hypoxia-inducible factor 1 negatively regulates Th1 function. J Immunol 195:1372–1376

    Article  CAS  PubMed  Google Scholar 

  42. Vuillefroy de Silly R, Ducimetiere L, Yacoub Maroun C, Dietrich PY, Derouazi M, Walker PR (2015) Phenotypic switch of CD8(+) T cells reactivated under hypoxia toward IL-10 secreting, poorly proliferative effector cells. Eur J Immunol 45:2263–2275

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We wish to thank the members of our laboratory Cory U. Lago, William M. Kamp, Jerry J. Li, and Jie Zhuang for the helpful assistance and critical comments. We also thank the mouse facility staff for the hypoxia chamber maintenance and Elias Gonzalez and Bruce Bishop for the technical assistance.

Author contributions

Authors responsible for concept and design were JGK, HS, JYK, PYW, and PH. JGK, HS, MJA, MP, MDA, AN, DS, JC, and JP contributed data. JGK, AR, AN, JP, JC, PYW, and PH were responsible in the analysis and interpretation of data. JGK, PYW, and PH drafted the manuscript.

Author information

Authors and Affiliations

  1. Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Ju-Gyeong Kang, Ho Joong Sung, Ji-hoon Park, Ping-yuan Wang & Paul M. Hwang

  2. College of Health Science, Eulji University, Seongnam, Korea

    Ho Joong Sung

  3. Cardiovascular-Pulmonary Branch, NHLBI, NIH, Bethesda, MD, USA

    Marcelo J. Amar, Milton Pryor & Alan T. Remaley

  4. Murine Phenotyping Core, NHLBI, NIH, Bethesda, MD, USA

    Michele D. Allen, Audrey C. Noguchi & Danielle A. Springer

  5. School of Medicine, Chungnam National University, Daejeon, Korea

    Jaeyul Kwon

  6. Hematology Branch, NHLBI, NIH, Bethesda, MD, Korea

    Jichun Chen

Authors
  1. Ju-Gyeong Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ho Joong Sung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marcelo J. Amar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Milton Pryor
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alan T. Remaley
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michele D. Allen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Audrey C. Noguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Danielle A. Springer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jaeyul Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jichun Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ji-hoon Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ping-yuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Paul M. Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul M. Hwang.

Ethics declarations

Study approval

All mice were maintained and handled in accordance with the NHLBI Animal Care and Use Committee. All human samples were obtained from healthy volunteers after informed consent as approved by the NHLBI Institutional Review Board.

Conflict of interests

The authors declare that they have no competing interests.

Sources of funding

Research supported by the Division of Intramural Research, National Heart, Lung, and Blood Institutes (NHLBI), National Institutes of Health.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 384 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kang, JG., Sung, H.J., Amar, M.J. et al. Low ambient oxygen prevents atherosclerosis. J Mol Med 94, 277–286 (2016). https://doi.org/10.1007/s00109-016-1386-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-016-1386-3

Keywords

Search

Navigation