title: Increased endothelial microparticles and oxidative stress at extreme altitude.
abstract: OBJECTIVE
  Hypoxia and oxidative stress affect endothelial function. Endothelial microparticles (MP) are established measures of endothelial dysfunction and influence vascular reactivity. To evaluate the effects of hypoxia and antioxidant supplementation on endothelial MP profiles, a double-blind, placebo-controlled trial, during a high altitude expedition was performed.
  
  
  METHODS
  29 participants were randomly assigned to a treatment group (n = 14), receiving vitamin E, C, A, and N-acetylcysteine daily, and a control group (n = 15), receiving placebo. Blood samples were obtained at 490 m (baseline), 3530, 4590, and 6210 m. A sensitive tandem mass spectrometry method was used to measure 8-iso-prostaglandin F2α and hydroxyoctadecadienoic acids as markers of oxidative stress. Assessment of MP profiles including endothelial activation markers (CD62+MP and CD144+MP) and cell apoptosis markers (phosphatidylserine+MP and CD31+MP) was performed using a standardized flow cytometry-based protocol.
  
  
  RESULTS
  15 subjects reached all altitudes and were included in the final analysis. Oxidative stress increased significantly at altitude. No statistically significant changes were observed comparing baseline to altitude measurements of phosphatidylserine expressing MP (p = 0.1718) and CD31+MP (p = 0.1305). Compared to baseline measurements, a significant increase in CD62+MP (p = 0.0079) and of CD144+MP was detected (p = 0.0315) at high altitudes. No significant difference in any MP level or oxidative stress markers were found between the treatment and the control group.
  
  
  CONCLUSIONS
  Hypobaric hypoxia is associated with increased oxidative stress and induces a significant increase in CD62+ and CD144+MP, whereas phosphatidylserine+MP and CD31+MP remain unchanged. This indicates that endothelial activation rather than an apoptosis is the primary factor of hypoxia induced endothelial dysfunction.
authors.affiliation: Department of Pneumology, University Hospital and University of Bern, Bern, Switzerland. Jacqueline.Pichler@Insel.ch.|Department of Intensive Care Medicine, University Hospital and University of Bern, Bern, Switzerland. Jacqueline.Pichler@Insel.ch.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Pichler Hefti
authors.affiliation: University Institute of Clinical Chemistry, University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Leichtle
authors.affiliation: Department of Clinical Investigation, University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Monika
authors.initials: M
authors.lastname: Stutz
authors.affiliation: Swiss Sportsclinic, Bern, Switzerland.
authors.forename: Urs
authors.initials: U
authors.lastname: Hefti
authors.affiliation: Department of Pneumology, University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Geiser
authors.affiliation: Center of Laboratory Medicine, Cantonal Hospital Aarau, Aarau, Switzerland.
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Huber
authors.affiliation: Department of Intensive Care Medicine, University Hospital and University of Bern, Bern, Switzerland.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Merz
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage / Q000627:therapeutic use; D000328:Adult; D000531:Altitude; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D055252:Cell-Derived Microparticles / Q000473:pathology*; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D011453:Prostaglandins / Q000097:blood; D014815:Vitamins / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D011453:Prostaglandins; D014815:Vitamins; D000111:Acetylcysteine
keywords: Endothelial dysfunction; Extreme altitude; Hypoxia; Microparticles; Oxidative stress
references.citation: Am J Physiol Lung Cell Mol Physiol. 2006 Dec;291(6):L1232-45
references.pmid: 16891393
references.citation: J Nutr. 1999 Nov;129(11):2009-12
references.pmid: 10539777
references.citation: J Biol Chem. 1991 Dec 25;266(36):24302-7
references.pmid: 1662206
references.citation: Am J Respir Crit Care Med. 2005 Sep 15;172(6):763-7
references.pmid: 15947284
references.citation: Thromb Haemost. 2003 Oct;90(4):698-703
references.pmid: 14515191
references.citation: Cell Physiol Biochem. 2015 ;35(6):2079-97
references.pmid: 25895668
references.citation: FASEB J. 2000 Apr;14(5):691-8
references.pmid: 10744626
references.citation: J Physiol. 2014 Mar 1;592(5):1009-24
references.pmid: 24324004
references.citation: Arterioscler Thromb Vasc Biol. 2006 Jan;26(1):112-6
references.pmid: 16239600
references.citation: Cardiovasc Res. 2010 Feb 1;85(3):582-92
references.pmid: 19710084
references.citation: Blood. 1997 Feb 15;89(4):1121-32
references.pmid: 9028933
references.citation: Circulation. 2001 Apr 24;103(16):2078-83
references.pmid: 11319198
references.citation: J Thromb Haemost. 2006 May;4(5):1003-10
references.pmid: 16689751
references.citation: Circulation. 2007 Mar 13;115(10):1285-95
references.pmid: 17353456
references.citation: J Cereb Blood Flow Metab. 2006 Jan;26(1):99-111
references.pmid: 15959459
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11715-20
references.pmid: 9751731
references.citation: J Heart Lung Transplant. 2009 Oct;28(10):1081-6
references.pmid: 19782291
references.citation: Respir Physiol Neurobiol. 2010 Dec 31;174(3):165-74
references.pmid: 20801239
references.citation: QJM. 2009 May;102(5):341-8
references.pmid: 19273551
references.citation: Br J Haematol. 2007 Apr;137(1):36-48
references.pmid: 17359370
references.citation: Circulation. 2001 Nov 27;104(22):2649-52
references.pmid: 11723013
references.citation: J Pharmacol Exp Ther. 2008 May;325(2):370-9
references.pmid: 18252813
references.citation: Circulation. 1997 Nov 18;96(10):3593-601
references.pmid: 9396460
references.citation: Thromb Haemost. 2011 Aug;106(2):310-21
references.pmid: 21713319
references.citation: Biofactors. 2006;27(1-4):195-202
references.pmid: 17012775
references.citation: Vascul Pharmacol. 2002 Nov;39(4-5):213-23
references.pmid: 12747961
references.citation: J Appl Physiol (1985). 1999 Jul;87(1):391-9
references.pmid: 10409600
references.citation: Br J Clin Pharmacol. 1996 Jul;42(1):15-9
references.pmid: 8807139
references.citation: FASEB J. 2004 Dec;18(15):1791-800
references.pmid: 15576482
references.citation: Nature. 2005 Sep 15;437(7057):426-31
references.pmid: 16163360
references.citation: Lancet. 1996 Mar 23;347(9004):781-6
references.pmid: 8622332
references.citation: Circ Res. 2008 May 23;102(10 ):1192-201
references.pmid: 18420943
references.citation: High Alt Med Biol. 2001 Spring;2(1):21-9
references.pmid: 11252695
references.citation: J Am Coll Cardiol. 2002 Mar 20;39(6):1072-7
references.pmid: 11897453
references.citation: J Thromb Haemost. 2012 May;10(5):919-30
references.pmid: 22394434
references.citation: Basic Res Cardiol. 2011 Nov;106(6):911-23
references.pmid: 21691898
references.citation: Swiss Med Wkly. 2010 Feb 20;140(7-8):111-7
references.pmid: 19950043
references.citation: Hypertension. 2007 Apr;49(4):902-8
references.pmid: 17309952
references.citation: J Physiol. 2010 Dec 1;588(Pt 23):4837-47
references.pmid: 20876202
references.citation: J Biol Chem. 1999 Sep 17;274(38):26736-42
references.pmid: 10480877
references.citation: Biochim Biophys Acta. 2008 Mar;1778(3):794-809
references.pmid: 17961505
references.citation: Methods Enzymol. 2007;433:113-26
references.pmid: 17954231
references.citation: Respir Res. 2014 Jun 14;15:65
references.pmid: 24929652
references.citation: Am J Respir Crit Care Med. 2008 Mar 1;177(5):536-43
references.pmid: 18006886
references.citation: PLoS One. 2015 Apr 13;10(4):e0121516
references.pmid: 25875611
references.citation: Platelets. 2007 Nov;18(7):515-21
references.pmid: 17957567
references.citation: Free Radic Biol Med. 2011 Sep 1;51(5):1000-13
references.pmid: 21664268
references.citation: Mol Biol Cell. 1998 Jun;9(6):1589-601
references.pmid: 9614196
references.citation: Lancet. 2000 Oct 7;356(9237):1213-8
references.pmid: 11072938
references.citation: J Appl Physiol (1985). 2001 Apr;90(4):1299-306
references.pmid: 11247927
references.citation: Cardiovasc Res. 2003 Aug 1;59(2):277-87
references.pmid: 12909311
references.citation: Clin Hemorheol Microcirc. 2015 ;61(1):83-90
references.pmid: 25322787
references.citation: Free Radic Biol Med. 2011 Apr 1;50(7):848-53
references.pmid: 21236333
references.citation: Am J Respir Crit Care Med. 2009 Feb 15;179(4):328; author reply 328-9
references.pmid: 19201930
references.citation: Circ Res. 2013 May 10;112(10):1323-33
references.pmid: 23536307
references.citation: Free Radic Biol Med. 2001 Dec 1;31(11):1456-64
references.pmid: 11728818
references.citation: Wilderness Environ Med. 2002 Summer;13(2):94-105
references.pmid: 12092978
references.citation: Am J Physiol Lung Cell Mol Physiol. 2003 Feb;284(2):L316-23
references.pmid: 12388340
references.citation: Circ Res. 1988 Apr;62(4):687-98
references.pmid: 3349572
references.citation: FASEB J. 2015 Mar;29(3):868-81
references.pmid: 25404710
references.citation: Am J Respir Crit Care Med. 2008 Jun 1;177(11):1268-75
references.pmid: 18310479
references.citation: Eur J Appl Physiol. 2014 May;114(5):1067-73
references.pmid: 24514947
references.citation: J Thromb Haemost. 2011 Jun;9(6):1216-24
references.pmid: 21481178
references.citation: Blood. 2001 Mar 15;97(6):1679-84
references.pmid: 11238107
references.citation: Nat Rev Mol Cell Biol. 2004 May;5(5):343-54
references.pmid: 15122348
references.citation: Biochim Biophys Acta. 2012 Jan;1821(1):241-7
references.pmid: 21763457
references.citation: Free Radic Biol Med. 1999 Jun;26(11-12):1501-7
references.pmid: 10401615
references.citation: Respir Physiol Neurobiol. 2007 Sep 30;158(2-3):128-31
references.pmid: 17482529
references.citation: Am J Respir Crit Care Med. 2010 Jul 15;182(2):261-8
references.pmid: 20339146
references.citation: Hypertension. 2012 Apr;59(4):818-24
references.pmid: 22353612
references.citation: Crit Care Med. 2011 Jul;39(7):1739-48
references.pmid: 21494101
references.citation: Circulation. 2004 Jan 20;109(2):159-65
references.pmid: 14734504
references.citation: Nat Med. 1998 Oct;4(10):1189-92
references.pmid: 9771755
references.citation: J Physiol. 2009 Jan 15;587(1):73-85
references.pmid: 18936082
references.citation: Nat Immunol. 2014 Mar;15(3):215-7
references.pmid: 24549064
references.citation: Cochrane Database Syst Rev. 2012 Mar 14;(3):CD007176
references.pmid: 22419320
references.citation: High Alt Med Biol. 2013 Sep;14 (3):273-9
references.pmid: 24067187
references.citation: Can J Cardiol. 2015 May;31(5):631-41
references.pmid: 25936489
references.citation: Am J Physiol Heart Circ Physiol. 2003 Aug;285(2):H875-82
references.pmid: 12730050
references.citation: BMC Neurosci. 2014 Sep 22;15:110
references.pmid: 25242463
references.citation: Thromb Res. 2003 Feb 15;109(4):175-80
references.pmid: 12757771