title: Low ambient oxygen prevents atherosclerosis.
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.
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ju-Gyeong
authors.initials: JG
authors.lastname: Kang
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.|College of Health Science, Eulji University, Seongnam, Korea.
authors.forename: Ho Joong
authors.initials: HJ
authors.lastname: Sung
authors.affiliation: Cardiovascular-Pulmonary Branch, NHLBI, NIH, Bethesda, MD, USA.
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Amar
authors.affiliation: Cardiovascular-Pulmonary Branch, NHLBI, NIH, Bethesda, MD, USA.
authors.forename: Milton
authors.initials: M
authors.lastname: Pryor
authors.affiliation: Cardiovascular-Pulmonary Branch, NHLBI, NIH, Bethesda, MD, USA.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.affiliation: Murine Phenotyping Core, NHLBI, NIH, Bethesda, MD, USA.
authors.forename: Michele D
authors.initials: MD
authors.lastname: Allen
authors.affiliation: Murine Phenotyping Core, NHLBI, NIH, Bethesda, MD, USA.
authors.forename: Audrey C
authors.initials: AC
authors.lastname: Noguchi
authors.affiliation: Murine Phenotyping Core, NHLBI, NIH, Bethesda, MD, USA.
authors.forename: Danielle A
authors.initials: DA
authors.lastname: Springer
authors.affiliation: School of Medicine, Chungnam National University, Daejeon, Korea.
authors.forename: Jaeyul
authors.initials: J
authors.lastname: Kwon
authors.affiliation: Hematology Branch, NHLBI, NIH, Bethesda, MD, Korea.
authors.forename: Jichun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ji-hoon
authors.initials: JH
authors.lastname: Park
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ping-yuan
authors.initials: PY
authors.lastname: Wang
authors.affiliation: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. hwangp@mail.nih.gov.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Hwang
mesh_terms: D000532:Altitude Sickness / Q000453:epidemiology* / Q000235:genetics / Q000276:immunology; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000276:immunology; D050197:Atherosclerosis / Q000453:epidemiology* / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000276:immunology; D007249:Inflammation / Q000453:epidemiology / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010100:Oxygen / Q000276:immunology*; D065840:Protective Factors; D015854:Up-Regulation
chemical_list: D001057:Apolipoproteins E; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016753:Interleukin-10; D010100:Oxygen
keywords: Anti-inflammatory; Atherosclerosis; Hypoxia; IL-10; Oxygen
references.citation: Am J Med Sci. 2002 Jan;323(1):3-10
references.pmid: 11814139
references.citation: Cell. 2003 Mar 7;112(5):645-57
references.pmid: 12628185
references.citation: Methods Mol Biol. 2015;1339:1-16
references.pmid: 26445778
references.citation: High Alt Med Biol. 2002 Winter;3(4):401-7
references.pmid: 12631426
references.citation: Mol Med. 2003 Jan-Feb;9(1-2):10-7
references.pmid: 12765335
references.citation: N Engl J Med. 1977 Mar 17;296(11):581-5
references.pmid: 840241
references.citation: Ann Emerg Med. 1987 Sep;16(9):974-9
references.pmid: 3307557
references.citation: Cell. 1993 Oct 22;75(2):263-74
references.pmid: 8402911
references.citation: J Biol Chem. 1996 Dec 20;271(51):32529-37
references.pmid: 8955077
references.citation: N Engl J Med. 1999 Jan 14;340(2):115-26
references.pmid: 9887164
references.citation: Atherosclerosis. 1999 Aug;145(2):301-8
references.pmid: 10488957
references.citation: Circ Res. 1999 Oct 15;85(8):e17-24
references.pmid: 10521249
references.citation: Nat Rev Immunol. 2005 Sep;5(9):712-21
references.pmid: 16110315
references.citation: Circ Res. 2005 Oct 28;97(9):922-7
references.pmid: 16179587
references.citation: Hypertens Res. 2005 Oct;28(10):837-45
references.pmid: 16471178
references.citation: N Engl J Med. 2006 Mar 16;354(11):1166-76
references.pmid: 16540617
references.citation: Scand J Immunol. 2006 Apr;63(4):304-10
references.pmid: 16623931
references.citation: Circ Res. 2006 May 26;98(10):1282-9
references.pmid: 16614304
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4547-52
references.pmid: 17360561
references.citation: PLoS One. 2007;2(9):e853
references.pmid: 17786224
references.citation: Cardiovasc Res. 2008 Aug 1;79(3):360-76
references.pmid: 18487233
references.citation: Crit Rev Immunol. 2008;28(4):281-99
references.pmid: 19166381
references.citation: Trends Immunol. 2009 Mar;30(3):102-8
references.pmid: 19201652
references.citation: Arterioscler Thromb Vasc Biol. 2009 May;29(5):665-70
references.pmid: 19251587
references.citation: Circulation. 2009 Aug 11;120(6):495-501
references.pmid: 19635973
references.citation: Nat Rev Immunol. 2010 Mar;10(3):170-81
references.pmid: 20154735
references.citation: Atherosclerosis. 2010 Apr;209(2):381-6
references.pmid: 19897196
references.citation: Circulation. 2010 Apr 27;121(16):1828-37
references.pmid: 20385932
references.citation: N Engl J Med. 2011 Feb 17;364(7):656-65
references.pmid: 21323543
references.citation: PLoS One. 2011;6(5):e19785
references.pmid: 21589870
references.citation: J Immunol. 2011 Sep 1;187(5):2696-701
references.pmid: 21784977
references.citation: Proc Natl Acad Sci U S A. 2012 Jan 24;109(4):1239-44
references.pmid: 22232678
references.citation: Curr Protoc Immunol. 2012 Feb;Chapter 15:Unit 15.24.1-23
references.pmid: 22314832
references.citation: J Card Fail. 2012 May;18(5):387-91
references.pmid: 22555269
references.citation: N Engl J Med. 2013 Mar 14;368(11):1027-32
references.pmid: 23484829
references.citation: Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17462-7
references.pmid: 24101519
references.citation: Immunity. 2014 Oct 16;41(4):518-28
references.pmid: 25367569
references.citation: Arterioscler Thromb Vasc Biol. 2014 Dec;34(12):2545-53
references.pmid: 25256233
references.citation: Thromb Haemost. 2015 Mar;113(3):505-12
references.pmid: 25373619
references.citation: Circulation. 2015 Jun 16;131(24):2143-50
references.pmid: 26002889
references.citation: J Immunol. 2015 Aug 15;195(4):1372-6
references.pmid: 26179900
references.citation: Eur J Immunol. 2015 Aug;45(8):2263-75
references.pmid: 25929785